ORIGINAL ARTICLE
Port wine stain treatment outcomes have not improved over
the past three decades
M.I. van Raath,
1,2S. Chohan,
2A. Wolkerstorfer,
3C.M.A.M. van der Horst,
4G. Storm,
5,6M. Heger
1,2,5,*
1Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China
2Department of Experimental Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands 3Department of Dermatology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands 4
Department of Plastic, Reconstructive, and Hand Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
5Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands 6
Department of Controlled Drug Delivery, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, the Netherlands
*Correspondence: M. Heger. E-mail: m.heger@uu.nl
Abstract
Background Since the early‘80s, the pulsed dye laser has been the standard treatment tool for non-invasive port wine stain (PWS) removal. In the last three decades, a considerable amount of research has been conducted to improve clinical outcomes, given that a fraction of PWS patients proved recalcitrant to laser treatment. Whether this research actually led to increased therapeutic efficacy has not been systematically investigated.
Objective To analyse therapeutic efficacy in PWS patients globally from 1986 to date.
Methods PubMed was searched for all available PWS trials. Studies with a quartile percentage improvement scale were included, analysed and plotted chronologically. Treatment and patient characteristics were extracted. A mean clearance per study was calculated and plotted. A 5-study simple moving average was co-plotted to portray the trend in mean clearance over time. The data were separately analysed for multiple treatment sessions in previously untreated patients.
Results Sixty-five studies were included (24.3% of eligible studies) comprising 6207 PWS patients. Of all patients, 21% achieved 75–100% clearance. Although a few studies reported remarkably good outcomes in a subset of carefully selected patients, there was no upward trend over time in mean clearance.
Conclusion The efficacy of PWS therapy has not improved in the past decades, despite numerous technical innovations and pharmacological interventions. With an unwavering patient demand for better outcomes, the need for development and implementation of novel therapeutic strategies to clear all PWS is as valid today as it was 30 years ago.
Received: 24 November 2018; Accepted: 7 March 2019
Conflict of interest
MH owns intellectual property rights to site-specific pharmaco-laser therapy (SSPLT). There are no other
financial arrangements or potential conflicts of interest related to this article.
Funding sources
MH wasfinancially supported by a preseed grant from the Academic Medical Center SKE Fund (Technostarter #
20090812) and a valorization grant from Stichting Technologische Wetenschap (STW, project # 12064).
Introduction
The introduction of the pulsed dye laser (PDL) in the early
‘80s revolutionized the treatment of port wine stains (PWS)
in terms of safety and efficacy. Subsequent clinical trials,
however, revealed that the underlying principle of PDL
ther-apy
– selective photothermolysis (SP) – was itself selective
for patients with a certain dermal vascular phenotype. As a
result, a substantial fraction of the PWS population still
suffered from suboptimal therapeutic outcomes. The years of
intense research that followed to further improve SP and
clinical outcomes yielded new PDL systems with longer
wavelengths (585 and 595 nm), longer pulse durations,
epidermal cooling modalities, different SP light sources and
novel approaches altogether such as photodynamic therapy
(PDT),
pharmacological
interventions
and
combination
treatments.
1,2© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd
In 2012, we published a comprehensive summary of clinical
results, which spawned the narrative that therapeutic efficacy
had not improved despite the multitude of innovations in the
field.
1In this article, we revisited that narrative and reanalysed
the clinical outcomes obtained to date in greater detail, also
including trial results achieved with more modern modalities.
The overall conclusion has not changed in the last 6 years: the
efficacy of clinically offered PWS treatment modalities has not
improved and approximately half of all PWS patients bear
lesions that are recalcitrant to the different forms of treatment.
This is disconcerting given the fact that research into novel
ther-apeutic avenues has abated, in part driven by a shift to different,
commercially more lucrative applications of biomedical lasers,
while the patients’ need for more effective interventions has
not.
3Methods
Advances in therapeutic efficacy were studied by comparing the
results of published clinical trials in a chronological context.
PubMed was searched for full-text PWS intervention studies
from 1986 (when the first clinical studies with PDL for PWS
appeared) to date. No restrictions were applied on the types of
studies and, where possible, non-English studies were
trans-lated. To enable comparative analysis, only studies that
employed the most common physician/investigator-reported
outcome scoring system were included, that is, those that
classi-fied results in quartiles of percentage lightening (i.e. 0–24%,
25–49%, 50–74% and 75–100%). Studies that reported an exact
percentage clearance per patient (0–100%) or used other classes
of percentage clearance that could be converted to the
afore-mentioned quartiles were also included. Many other studies
classified outcomes into ‘poor’, ‘fair’, ‘good’ and ‘excellent’, but
the exact definitions for these classes vary widely and studies
using non-compliant scoring systems were excluded.
4Studies
and treatment arms with less than five PWS patients were
excluded. ‘Treatment arm’ refers to a patient cohort where one
particular treatment modality was used. For example, a study
comparing 577-nm PDL to 585-nm PDL comprised two
treat-ment arms. In studies that compared different settings (e.g.
pulse duration, fluence) within one laser system, only the
treat-ment arm with the highest efficacy was included. Information
on the study population, type of intervention(s) and lesion
characteristics was extracted. Different treatment arms within
one study were analysed separately.
In the first analysis, all included studies were clustered to
paint a complete picture of PWS treatment outcomes over time.
Inasmuch as the first analysis revealed no improvement in
treat-ment outcomes over time, a second analysis was performed
where studies were filtered based on prospective vs. retrospective
trials, single vs. multiple treatment sessions and history of
previ-ous treatment vs. untreated PWS. The second analysis was
per-formed to assess treatment outcome progress in better-matched
patient cohorts, thereby eliminating the possibility that clinical
variables potentially responsible for deterring improvement in
treatment outcomes would statistically affect those variables that
did not, and thus falsely skew progress data. Studies in which less
than 10% of patients had received previous treatment were
sorted into the ‘untreated’ group for purposes of simplifying the
analysis. In the group of ‘multiple treatment’ studies, patients
were offered more than one treatment session.
In addition to analysing the stratified outcomes of individual
treatment arms, the overall result per outcome category of all
studies was calculated (i.e. for all included patients per category).
To this end, a mean score that represents the result of the entire
study population (H) was calculated per outcome category using
Eqn (1),
Hð%Þ ¼ 100
j
k
ð1Þ
where j is the number of subjects in the selected (quartile)
cate-gory (extracted from all studies), and k is the total number of
subjects in all studies. The stratified outcomes of individual
treatment arms, filtered treatment arms and overall result per
outcome category of all studies were plotted in bar charts.
To graphically monitor and compare overall study outcomes
in chronological order, a mean clearance score per study or
treatment arm (Cl) was calculated in the third analysis using
Eqn (2),
Cl
ð%Þ ¼
12:5d þ 37:5e þ 62:5f þ 87:5g
100
ð2Þ
where d, e, f and g represent the percentage of patients with 0–
24%, 25–49%, 50–74% and 75–100% clearance, respectively.
The values for d, e, f and g were extracted (or calculated if
possi-ble where not reported) from the included studies. Note that, as
a corollary of this mathematical method, the minimum and
maximum values for Cl are 12.5% and 87.5%, respectively.
Finally, it was hypothesized that all the compounding research
would lead to a gradual, non-incidental improvement in clinical
outcomes over time, and that this would be reflected by an
increasing Cl with the number of studies published. Accordingly,
a five-study/treatment arm simple moving average for clearance
(Cl
m) was calculated in the fourth analysis by averaging the Cl of
a study in the chronological sequence of studies (n) and the
mean clearance scores of its four preceding studies (1, 2,
n-3, n-4), according to Eqn (3).
Cl
mð%Þ ¼
Cl
nþ Cl
n1þ Cl
n2þ Cl
n3þ Cl
n45
:
ð3Þ
The principle of the simple moving average was borrowed
from the technical analysis of financial markets, where simple
moving averages are employed to gauge trends in stock prices by
filtering out the noise in momentary price fluctuations.
5The
number of studies/treatment arms included in the moving
aver-age was set to five as this number was determined to be
suffi-ciently high to offset volatility due to incidental outliers but not
too high to obscure actual treatment improvement trends. The
Cl and Cl
mwere plotted in a line graph.
All plotted variables were evaluated for trends using visual
inspection first. If an upward trend was asserted, regression
anal-ysis (Theil-Sen estimator for non-parametric data) and
Spear-man correlation analysis were performed.
Results
The global clinical reality in the face of 30 years of technological innovations
Our search resulted in 931 PubMed records published since 1986.
After screening, studies were excluded because of the use of
non-compliant outcome scoring systems (N
= 132), insufficient
report-ing of the data (when a compliant outcome scorreport-ing system was
used; N
= 32), unavailability of full text (N = 27), paper could
not be translated (N
= 11) or because less than five patients were
included (N
= 42). Additional studies were excluded (N = 622)
because of other reasons, mainly including the study did not
involve PWS patients, no or unclear intervention and no
assess-ment of treatassess-ment efficacy. A total of 65 full-text studies (i.e.
24.3% of eligible studies) comprising 6207 patients and 73
treat-ment arms met the inclusion criteria and were included in the
analysis. The data encompass prospective and retrospective studies,
different types of lasers and laser settings, various patient
popula-tions (with differences in age, skin phototypes, etc.), various
lesions (hypertrophic or flat, pink or purple, etc.), untreated
patients and previously treated or even therapy-resistant patients,
and single and multiple treatment sessions (summarized in
Table 1).
In the first analysis, the data were unclustered to reflect the
clinical reality in its broadest sense (Fig. 1a).
6–70In terms of
interventions, a rapid switch from the 577-nm PDL to
longer-wavelength (585 and 595 nm) PDLs is noted. Concurrently, the
copper vapour laser was abandoned. Around the year 2000, a
diversification in light sources occurred as the 532-nm Nd:YAG/
potassium titanyl phosphate (KTP) laser and intense pulsed light
(IPL) were introduced in the experimental clinical setting.
Around the same time, cryogen spray cooling technology was
implemented. In the last decade, almost all laser therapies have
been performed in conjunction with some form of epidermal
cooling. During the last 15 years, various combinatorial
treat-ments, such as the concomitant use of the PDL and Nd:YAG
laser, have been studied. Also, hematoporphyrin monomethyl
ether and other photodrugs have been explored as
photosensitiz-ers in PDT-based PWS treatment.
With respect to clearance rates, the most striking result is
that the data do not reveal a general improvement in
treatment outcomes upon visual inspection (hence no
fur-ther trend analysis with statistical methods was performed).
This is mainly evidenced by the visually narrowing white
area in time (Fig. 1a), indicating that the fraction of
patients with 75–100% clearance is not getting larger
towards present day while new technologies enter the
clini-cal setting and mature. One would expect a visually
broad-ening impression of the white region from left to right if
the introduction of novel technologies had actually
trans-lated to improved treatment efficacy, having resulted in a
gradually larger fraction of patients exhibiting the highest
level of clearance. A concurrent tapered pattern over time
would also be expected in the other (coloured) categories,
but such an effect is absent. The two studies from Anolik
et al. and Chapas et al. stand out because of their superior
results.
33,48This is likely a result of highly specific patient
selection inasmuch as these studies focused exclusively on
facial PWS in children
≤16 weeks or ≤6 months of age,
which is an age category and lesion location typically
associ-ated with good treatment efficacy.
57,71Innovations in PWS treatment modalities also get lost in translation in more case-matched analysis
To make a more valid comparison of treatment results in time,
trials were analysed in which previously untreated patients
received multiple treatments (Fig. 1b) and where retrospective
studies were excluded from the trials where previously
untreated patients received multiple treatments (Fig. 1c). The
overall scores included in all panels (which weigh data based on
cohort size) show that the best results were achieved in the
prospective studies with previously untreated patients, with
30.5% of all included patients having 75–100% clearance (vs.
21.4% and 17.0% for Fig. 1 panel a and b, respectively).
Never-theless, no improvement in treatment efficacy over time is
noted in either analysis when the data are interpreted in
chronological context as explained above (section The global
clinical reality in the face of 30 years of technological
innova-tions).
As in the clustered data set (Fig. 1a), the proportion of
patients in the more case-matched studies that achieved the
desired outcome (75–100% clearance) and suboptimal outcomes
(25–49% and 50–74% clearance) has not notably changed over
the last three decades (Fig. 1b,c). In fact, only a handful of
stud-ies report a greater proportion of 75–100% clearance than the
studies performed in 1988–1991. The proportion of patients
with the worst outcome (0–24% clearance) is 0% in a few
stud-ies, but remains substantial in most (Fig. 1a–c). These
observa-tions are further echoed by the fact that most of the outcome
category bars in individual studies/treatment arms are larger
than the respective bar of the overall result per outcome category
of all studies (most right bar in Fig. 1a–c), reflecting a worse
outcome than the mean.
Trend analysis affirms the absence of treatment efficacy improvement over time
To put the data in better perspective, the outcomes of all
included studies were converted into an average clearance score
per study (Cl) and plotted as a function of time. Additionally, a
five-study/treatment arm simple moving average (Cl
m) was
cal-culated for each of the subsets from Fig. 1 (average time span:
2.5, 5.5 and 9.3 years for Fig. 2a–c, respectively) to ameliorate
the effect of incidental outliers on the mean treatment outcomes.
What becomes evident from Fig. 2a–c is that, although the
mov-ing averages resemble a sinusoidal waveform, neither trace
exhi-bits a long-term upward trend, yielding credence to the previous
conclusions.
It could be argued that some studies may have achieved
rela-tively poor outcomes as a result of study design, for example, by
inclusion of patients with difficult-to-treat dark skin or
hyper-trophic PWS. When studies with the highest average clearance
scores only are considered, however, nothing changes in the
trend and therefore this argument does not hold.
Table 1 Study characteristics
All studies (N = 65 publications) Country where study
was performed,N (%) China 15 (23.1), USA 10 (15.4), UK 9 (13.8), Japan 3 (4.6), Germany 7 (10.8), Korea 4 (6.2), Turkey 3 (4.6), Switzerland 2 (3.1), Iraq 2 (3.1), Denmark 2 (3.1), India 2 (3.1), Singapore 1 (1.5), Slovenia 1 (1.5), Poland 1 (1.5), Spain 1 (1.5), Italy 1 (1.5), Taiwan 1 (1.5) Treatment centres,N 59 Therapy,N (% of treatment arms,N = 73†) PDL 577 nm 1 (1.4) 585 nm 17 (23.3) 595 nm 16 (21.9) 577 nm or 585 nm 1 (1.4) 585 nm or 595 nm 1 (1.4) 585 nm and/or 595 nm 1 (1.4) Nd:YAG 532 nm 11 (15.1) 1064 nm 5 (6.9) PDL (585 nm) and/or Nd:YAG (532 nm) 1 (1.4) Alexandrite (755 nm) 2 (2.7) IPL (various wavelengths) 8 (11.0) CVL (511+ 578 nm) 1 (1.4) PDT HMME (510.6 nm+ 578.2 nm) 2 (2.7) Combinatorial modalities Nd:YAG (1064 nm+ 532 nm) 1 (1.4) DL (800 nm)+ PDL (585 nm) 1 (1.4) PDL (595 nm)+ Nd:YAG (1064 nm) 3 (4.1) ICG+ DL (800 nm) 1 (1.4) Age category,N (%) <18 years only 6 (9.2) >18 years only 13 (20.0) All ages 46 (70.8) Previous treatment,N (%) Yes 19 (29.2) No 27 (41.5) Applied in<10% of patients 4 (6.2) NL 15 (23.1) PWS localization,N (%)
Face and neck only 10 (15.4)
Face only 13 (20.0) Extremities 2 (3.1) Various 37 (56.9) NL 3 (4.6) Table 1 Continued All studies (N = 65 publications) PWS types,N (%)
Flat lesions only 25 (38.5) Therapy-resistant only 5 (7.7) Hypertrophic only 2 (3.1) Hypertrophic or therapy-resistant 2 (3.1)
Various 11 (16.9)
NL 20 (30.7)
Cooling,N (% of laser applications, N = 80†)
Contact cooling 15 (18.8) Cryogen spray cooling 30 (37.5) Air cooling 7 (8.8) No cooling 28 (35.0) Study design,N (%) Prospective 46 (70.7) Retrospective 19 (29.2) Number of treatments,N (%)
Multiple treatment sessions 53 (81.5) Single treatment 11 (16.9)
NL 1 (1.5)
†Discrepancy between the number of treatment arms (73), the total number of studies (65) and the number of laser applications (80) stems from the fact that some studies encompassed multiple therapies and dual light source applications.
CVL, copper vapour laser; DL, diode laser; HMME, hematoporphyrin mono-methyl ether; ICG, indocyanine green; IPL, intense pulsed light;N, sample size; Nd:YAG, neodymium-doped yttrium aluminium garnet; NL, not listed; PDL, pulsed dye laser; PDT, photodynamic therapy; PWS, port wine stain.
In summary, only few studies in the past 20+ years have
been able to match or exceed the results obtained with the
577- and 585-nm PDL in the ‘80s and early ‘90s. None of
the technological innovations seem to have materialized
clini-cally in a beneficial manner for patients in terms of PWS
clearance.
<25% 25-49% 50-74% Clearance: 577 nm P DL 577 or 585 nm PD L 585 nm PD L 51 1 + 578 nm CV L 5 3 2 n m Nd :Y AG wi th CC 585 nm PD L 595 nm PD L w ith CSC 585 nm P DL wi th CSC 585 nm PD L 550-1 0 0 0 nm IPL 595 nm PD L w ith CSC 5 85 n m IP L 595 nm P D L w ith CSC 10 6 4 nm N d: Y AG w ith C S C 5 1 5-1 2 0 0 n m I P L HMME PD T 595 nm PD L w ith CSC 515-12 00 nm IPL 59 5 nm PD L wi th C S C 1 0 64 nm N d :YA G wi th CC 595 nm PD L w ith CSC 59 5 nm PD L w it h CSC 5 9 5 n m PDL + 1064 nm Nd:Y AG wi th AC 532 nm N d :Y AG wi th C C 1 0 64 n m N d:Y A G w it h C C 595 nm PD L w ith CSC 0 10 20 30 40 50 60 70 80 90 100 Garden ( 1 988) Reyes (1 990 ) As hin o ff (199 1) Chung (1997) Du mmer (199 8) Somme r (2 000 ) Chang (2002) Cha ng (200 2) Sommer ( 20 0 3 ) Reynolds (2 0 05 ) Woo (200 6) Özdemir (2008) Chapas (2007) Ko no (2 009 ) Do ng (2 010 ) Xi ao (201 1) An o li k ( 2 0 1 2 ) Wang ( 201 3 ) Shi (201 4) Z h o n g (201 4) Ren (2014) Liu (20 1 5) Tu (201 5) Al -Dha li m i (20 1 6 ) Al -D hali mi ( 2 0 16) Zh u ( 2 0 1 8 ) Ove rall result Patients (%) 577 nm PD L 577 or 585 nm PD L 585 nm PD L 585 nm PD L 51 1 + 578 nm CVL 532 nm N d :Y A G w ith CC 585 nm PD L w ith CSC 585 nm PD L 532 nm N d :Y A G w ith CC 585 nm PD L 585 nm PD L 5 3 2 n m N d :Y A G 585 nm PD L 5 85 a nd /o r 5 9 5 n m P DL wi th CSC 585 nm PD L (n=36), 532 nm N d :Y A G (n=40), both (n=31) 59 5 nm PD L w it h CS C 585 nm PD L w ith CSC 585 nm PD L 585 nm PD L 5 3 2 n m Nd :Y AG (v ar iou s setting s) wi th CC 595 nm PD L w ith C SC 585 nm PD L 585 nm PD L 555-95 0 nm IPL 10 6 4 + 53 2 n m Nd :Y AG wi th C S C 532 nm N d :Y A G w ith C SC 58 5 nm PDL 0. 5 ms wi th A C 5 95 n m P D L 2 0 m s w it h AC 5 50 , 57 0 , 590 n m I P L 5 95 n m P DL w ith CSC 5 32 n m N d :YA G wi th CSC 550-10 00 nm IPL 53 2 nm N d :Y A G 53 2 nm N d :Y A G wi th C C 585 o r 5 9 5 n m P DL wi th CSC 5 95 n m P DL wi th C SC 595 nm PD L w ith CSC 595 nm PD L w ith CSC 595 nm PD L w ith CSC 5 8 5 n m PDL wit h AC 585 nm PD L w ith CSC 595 nm PD L w ith CSC (variable p ul se ) 5 8 5 n m I P L 8 0 0 nm DL wi th C C + 5 8 5 n m P DL 1064 nm N d :Y A G wi th C S C 1064 nm N d :Y A G w ith CC 59 5 nm PD L + 1 06 4 n m Nd :Y AG w it h AC 56 0 , 5 90 , 6 4 0 n m I P L wi th C C 500 -6 7 0 & 870 -14 00 nm IPL w ith V S H and CC 515-12 0 0 nm IPL w ith CC HM M E PDT 10 6 4 nm N d :Y AG wi th C C 595 nm PD L w ith CSC 515-12 00 n m I PL 532 n m Nd :Y AG wi th CC 5 85 n m P D L w ith CSC ICG + 808 nm D L 595 nm PD L w ith CSC 595 nm PD L w ith CSC 585 nm PD L HMME PD T 1 06 4 nm Nd :Y A G wi th CC 5 9 5 n m P D L w it h C S C 595 nm PD L 5 95 n m P DL + 1064 n m Nd :Y AG w it h A C 7 55 n m A le xandr it e wi th C S C 5 3 2 n m Nd :Y AG wi th CC 1 0 6 4 n m Nd :Y AG wi th CC 59 5 n m PD L wi th C S C + 1 0 6 4 n m N d :Y AG wi th CSC 595 nm PDL with CSC 755 nm A lexandri te w ith CSC 532 nm N d :Y A G w ith CC 595 nm PDL with CSC 0 10 20 30 40 50 60 70 80 90 100 Gar d en ( 1 988) Re y es (1 990 ) As hin o ff (199 1) Lani gan ( 19 9 6 ) Chu n g (1 997 ) Du mmer (199 8) Chang (199 9) Som me r ( 2 0 0 0 ) Chan (2000) Go h (20 0 0) Wi m mer sho ff ( 20 0 1 ) Cho w dhu ry (20 0 1) Gr ev e ( 2 0 0 1 ) Kell y (2 002 ) Ho ( 200 2) Chang (200 2) Cha n g (2 0 02 ) Ackermann (2002) L or enz ( 2 0 0 3 ) L o ren z ( 2 003 ) Laub e (200 3) S o mmer ( 2 003 ) Woo (200 3) Bje rr in g (2 0 03 ) Ah can (200 4) Ah ca n (200 4 ) Greve (2004) Greve (2004) Ho (200 4) Wo o (2 0 0 4 ) Woo (2004) Reyno lds (200 5 ) Latk ows k i (200 5) P ence (2005) Kell y (2 005 ) To m so n ( 20 0 6 ) Woo (200 6) As ah in a ( 2 0 0 6) Chapas (2007) Ha mm es (2 0 0 7 ) Sharma ( 2 007 ) Ko no (2 007 ) Özdemir (2008) Whang (2009) Ko no ( 2 009 ) Civ as (200 9) Al st er (20 0 9 ) Li (201 0) Ad at to ( 2 0 1 0) Do ng (2 010 ) X ia o (201 1 ) Lee (20 12) An o lik ( 2 0 1 2 ) Wa n g (201 3) Reddy (201 3) Kl ei n ( 2 013 ) Kl ei n (2 013 ) Ren (2014 ) Shi (2014) Zh an g (20 14) Zh an g (20 1 4) Zh ong (201 4 ) Li u (20 1 5) Y ang (201 5) T u ( 2 0 1 5 ) Gri llo (201 6) Al -Dhali m i (2 01 6 ) Al-Dhalim i ( 2 0 16) B en ci ni ( 2 0 16) Kh an dpu r (201 6) Carl sen (2 017 ) Al -Janabi (201 7) Zh u (20 18) Ove rall result Patients (% ) 5 7 7 n m PD L 57 7 or 58 5 nm PD L 585 nm PD L 5 1 1 + 57 8 nm C VL 53 2 nm N d :Y A G wi th CC 5 85 n m PD L 5 5 0-10 00 nm IPL 585 nm I P L 1 0 6 4 n m Nd :Y AG wi th CSC 515-12 00 nm IPL 515-1 2 00 nm IPL 595 nm PDL with CSC 595 nm PD L + 1064 nm N d :Y A G w ith A C 5 32 n m N d :YA G wi th C C 1064 nm N d :Y A G w ith CC 595 nm PDL with CSC 0 10 20 30 40 50 60 70 80 90 100 Garden (1 988 ) Re ye s ( 1 9 9 0 ) As hi no ff ( 199 1 ) Chun g (19 9 7) Du mmer (199 8 ) Sommer ( 2 000 ) Rey n ol d s (200 5 ) Öz d em ir ( 20 0 8 ) K on o (20 0 9) D o n g (2 010 ) W ang (2013) Ren (201 4 ) Tu (201 5) Al -D h ali mi ( 20 1 6 ) Al -D h ali m i ( 2 0 16) Z hu ( 20 18) O v er al l r esul t Patients (%)(a)
(b)
(c)
Figure 1 Clearance rates reported in port wine stain studies published since 1986. Panel (a) shows all studies. Panel (b) includes only studies in which previously untreated patients were given multiple treatments. In panel (c) retrospective studies were excluded from the panel (b) data set. The clearance rates are stratified in quartiles according to the legend (bottom) and presented in chronological order. Every bar represents one study or one treatment arm. The respective year of publication andfirst author are referenced below the bar. The treatment specifics are listed in or above the bar. The proportion of patients is plotted on the y-axis, with 100% representing all the patients in the study or treatment arm. Note that the white area above each column represents the fraction of patients in the 75–100% clearance category. The column on the far right comprises the overall result per outcome category based on the overall study population. AC, air cooling; CC, contact cooling; CSC, cryogen spray cooling; CVL, copper vapour laser; DL, diode laser; HMME, hematoporphyrin monomethyl ether; IPL, intense pulsed light; Nd:YAG, neodymium-doped yttrium aluminium garnet; PDT, photodynamic therapy; PDL, pulsed dye laser; VSH, vascular-specific handpiece.
Discussion
The selective destruction of superficial hyperdilated dermal
vasculature has been subject to much research since the
inception of SP by Anderson and Parrish in 1983.
72A large
portion of the research that drove the technological and
con-ceptual innovations to optimize SP was based on
fundamen-tal principles related to the optical and thermal responses of
laser-irradiated dermal tissue. Mathematical modelling of
these responses brought about a shift to longer wavelengths,
longer pulse durations and larger spot sizes, which ultimately
had to be accommodated by epidermal cooling to counter
thermal skin damage. Unfortunately, the (patho)biology in
the skin heeded little attention to the vast number of
photo-physical and thermodynamic elaborations, leaving the field
with little or no improvement in PWS clearance in over three
decades and the patients with unresolved medical issues. This
Mean clearance Moving average
(a)
(b)
(c)
0 10 20 30 40 50 60 70 80 90 100 Ga rden (1 988 ) Reyes (1990) As hi no ff (199 1 ) Lani gan (1 996 ) C h un g ( 19 9 7) Du m mer (199 8) Chang (1999) So m m er (2 0 0 0 ) Chan (2000) Go h (2000) Wi mm er sho ff (2 001 ) Ch ow dhu ry ( 2 00 1) Greve (20 01) Kell y (2 002 ) Ho (200 2) Chang (200 2) Ch ang (2 0 02 ) Ackermann (2 002 ) L o re n z (2 003 ) Lo ren z (2 003 ) Laub e (200 3) Som m er (2 0 03 ) Woo (200 3) Bjerring (2003) Ah can ( 2 0 04 ) Ah can (200 4) Gr ev e ( 2 0 0 4 ) Greve (20 04) Ho (200 4) Woo (200 4) Woo ( 20 04 ) Reynolds (2005) Latk ows k i (200 5) Pe n ce (20 05 ) Kell y (20 0 5 ) To ms on (2 00 6 ) Woo (200 6) As ah in a (2 0 0 6) Cha p as (2007) Hamm es (20 07 ) S h ar m a (2 0 0 7) Ko no (2 007 ) Öz demir ( 2 008 ) Whan g (20 0 9) Ko no (2 009 ) Ci va s (2 0 09 ) Al st er (20 0 9) Li ( 2 0 10 ) Ad at to (201 0) Do n g ( 20 1 0 ) Xi ao (201 1) Lee (20 1 2) An ol ik ( 2 0 12) Wang (201 3) Red d y (201 3 ) Kl ei n (2 013 ) K le in (20 1 3) Ren (2014) Shi (2014) Z ha n g ( 20 1 4 ) Zh an g (20 14) Z h o n g (2 0 14 ) Li u (20 15) Yang (201 5) Tu (201 5) Gr il lo (2 0 1 6 ) A l-D h al im i (2 01 6 ) A l-D h alim i ( 20 16) Bencini (2016) Kh an d pu r (2 0 16 ) C arl se n (2 017 ) Al -Janabi (201 7) Z h u ( 20 1 8 ) Lightening (% ) 0 10 20 30 40 50 60 70 80 90 100 G ar d en (1 98 8 ) Reyes (1 990 ) A s h in o ff ( 1 9 91 ) Chu n g ( 1 99 7) D u m m er ( 1 9 98 ) Somm e r (2 000 ) Ch a ng ( 2 0 0 2 ) Chan g (20 02) Sommer (2 003 ) Reyn olds (200 5) W oo ( 2 0 06 ) Özdemir ( 2 00 8) C h a p as ( 2 00 7 ) Kono (20 09) Don g ( 2 01 0 ) Xia o (2011) A n ol ik (2 0 1 2) Wang (20 13) Shi ( 2 01 4 ) Zhon g (20 14) R en ( 2 0 14 ) Li u (2 01 5 ) Tu ( 2 01 5 ) Al-D halimi (2016) Al-D halimi (2016) Zhu (2 018 ) Li g h te nin g ( % ) 0 10 20 30 40 50 60 70 80 90 100 G a rde n (19 8 8 ) R ey es (1 9 9 0) Ashino ff (1 991 ) Chu ng (199 7) Dumme r (199 8 ) S o mm er (2 000 ) Rey n old s (2 00 5 ) Özdemir (200 8) Ko n o ( 2 00 9 ) D ong ( 2 0 1 0 ) Wang ( 2 0 1 3) Ren (2 014 ) Tu ( 2 01 5 ) A l-D h ali m i ( 2 01 6) A l-D halimi (20 1 6) Zhu (2 0 1 8 ) Light enin g (%)Figure 2 The mean clearance score per study or treatment arm (Cl; black line) and thefive-study/treatment arm simple moving average for clearance (Clm; blue dotted line) are plotted in chronological order. The panels (a–c) correspond to the panels and data subsets in Fig. 1.
is especially disappointing considering the long-term risk of
PWS redarkening and tissue hypertrophy.
73Moreover, our
analysis unveiled that SP and current treatments modalities
are intrinsically limited in their capacity to clear all PWS,
74leaving a substantial proportion of patients with no
alterna-tive treatment options. All the while, patient demand for
improved therapies has not abated, which is hardly surprising
considering the reduced quality of life that PWS patients
experience.
3,75,76It is therefore vital that new therapeutic strategies are adopted
using different approaches, where emphasis is placed on the
underlying (patho)biology rather than photophysics per se. In
light of this, the recent discovery that PWS vasculature is
charac-terized by differentiation-impaired endothelial cells that
co-express the arterial and venous markers ephrin receptor B1 and
ephrin B2 (probably as a result of sporadic somatic mutations in
the GNAQ gene)
77,78may lead to pharmacological modulators
that stimulate the normal differentiation of PWS endothelial
progenitor cells.
79In the future, these could potentially be used
to ensure normal development of dermal vascular plexi
post-treatment and improve post-treatment outcomes. In addition,
site-specific pharmaco-laser therapy may constitute a promising
treatment modality designed to target therapy-resistant blood
vessels by augmenting laser-induced thrombosis and complete
lumenal occlusion of PWS vasculature. Laser-induced
thrombo-sis is a biological response to SP in incompletely
photocoagu-lated blood vessels,
80while the complete occlusion of target
vessels is considered a clinical end point for complete PWS
clear-ance.
81Lastly, there are some limitations to the study that warrant
contextualization of the conclusions. First, the data are
incom-plete as studies that used other outcome scoring systems were
excluded (because of this, for example, no studies with
pharma-cological interventions could be included). Second, trial results
do not directly represent non-trial clinical results insofar as
bet-ter outcomes may be achieved in individual patients with the use
of varying lasers and laser settings. The physicians’
experience-based improvisations are not accounted for in the rigorous
design of clinical trials. Third, the study outcomes do not take
into consideration other important therapy aspects, such as
patient discomfort or adverse effects.
In conclusion, the efficacy of PWS therapy in clinical trials
has not improved in the past decades and remains limited,
despite technical innovations. With an unwavering patient
demand for better solutions, the need for development and
implementation of novel therapeutic strategies is as valid today
as it was 30 years ago.
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