Electrosclerotherapy for capillary malformations: study protocol for a randomised within-patient controlled pilot trial

Current status-of-the-
The ART treatment mode of fat vascular malformation (CMs)
Laser therapy, there are quite a few
Response and recurrence.
Injection of boleyin (
Or \"hardened \")
It is usually used for the treatment of venous and lymphatic malformation, and the effect is excellent, but due to the small diameter of the blood vessels, it is not possible to perform these intra-vascular injections in CMs.
Electrical perforation-
The electric field applied to the tissue-
The permeability of endothelial cells can be increased, and in theory the delivery of targeted local boleyin can be promoted.
Therefore, we assume that the injection of boleyin combined with electropuncture-
Treatment of electrical hardening (EST)
Also known as \"chemotherapy\"
May be a new alternative treatment option for CMs.
This method and analysis within random
A patient-control trial will register 20 patients with large CMs.
Three areas of interest (ROIs)
Randomly assigned to within CM (A)EST, (B)
Without electrical perforation and (C)no treatment.
Patients and outcome assessors turn a blind eye to treatment allocation.
Treatment results for each ROI will be treated with the patient approximately 7 weeks after the treatment procedure-
Report and doctor
Global Assessment scores, color studies, laser spot imaging, and adverse event reports reported.
The research programme was approved by the ethics review committee of the Amsterdam Academic Medical Center.
Results will be published in the peer
It will also be published at international conferences and scientific conferences.
The results of the study will be fed back to the patient population via website and social media notifications.
Trial registration number NCT02883023; Pre-results. NTR6169.
Current status introduction-of-the-
The ART treatment mode of fat vascular malformation (CMs)
Laser therapy, there are quite a few
Response and recurrence.
Injection of boleyin (
Or \"hardened \")
It is usually used for the treatment of venous and lymphatic malformation, and the effect is excellent, but due to the small diameter of the blood vessels, it is not possible to perform these intra-vascular injections in CMs.
Electrical perforation-
The electric field applied to the tissue-
The permeability of endothelial cells can be increased, and in theory the delivery of targeted local boleyin can be promoted.
Therefore, we assume that the injection of boleyin combined with electropuncture-
Treatment of electrical hardening (EST)
Also known as \"chemotherapy\"
May be a new alternative treatment option for CMs.
This method and analysis within random
A patient-control trial will register 20 patients with large CMs.
Three areas of interest (ROIs)
Randomly assigned to within CM (A)EST, (B)
Without electrical perforation and (C)no treatment.
Patients and outcome assessors turn a blind eye to treatment allocation.
Treatment results for each ROI will be treated with the patient approximately 7 weeks after the treatment procedure-
Report and doctor
Global Assessment scores, color studies, laser spot imaging, and adverse event reports reported.
The research programme was approved by the ethics review committee of the Amsterdam Academic Medical Center.
Results will be published in the peer
It will also be published at international conferences and scientific conferences.
The results of the study will be fed back to the patient population via website and social media notifications.
Trial registration number NCT02883023; Pre-results. NTR6169.
Vascular Malformation (CMs)
It is a congenital abnormality of skin capillaries, also known as \"port\"
Wine staining occurred in 3-5 of about 1000 newborns.
1-3 of these benign vascular birthmarks, nipples and ectatic dermal capillaries in the middle and small veins in the posterior dermal veins
The mesh layer of the skin causes a typical red color.
According to the recent classification of vascular abnormalities by the International Society for Vascular abnormalities, CMs is classified as \"vascular malformation\" and other types of vessels with congenital abnormal development: venous malformation, lymphatic and venous malformation.
Although CMs is usually light red and flat in young children, these birthmarks may develop into dark red or purple lesions with age and are nodules.
The cause of CMs is not yet known, but it is suspected that there is a lack of neural regulation of vascular flow.
Some genetic mutations are related to CMs.
The RASA1 gene mutation is associated with CM-venous malformation syndrome, and the recently discovered GNAQ mutation may be a major genetic determinant of isolated CMs.
9 10 CMs can be associated with a wide range of syndrome such as Sturge-
Weber syndrome occurs in the combination of facial CMs with the veins of the brain and eyes and CMs.
In addition to the makeup burden, CMs can also cause physical discomfort, such as bleeding due to obesity or oppression of facial structure.
The stigma of disfigurement CM can cause serious psychological burden and decline in quality of life.
Many treatments have been used to treat CMs in the last century, such as laser therapy, selective photo-thermal therapy, and skin cooling
The results were disappointing.
14 out of 1985, pulse-dye laser (PDL)
Since then, the therapy has been considered national. of-the-
Art therapy model of CMs.
2 14 in laser treatment, abnormal blood vessels are photocoagulation when the covered skin is preserved.
Some other less widely accepted treatments, such as photodynamics therapy and intense pulse light, are described in the literature, but the evidence suggests that these treatments are below the gold standard of laser therapy.
2 Although PDL is the only widely accepted treatment option for CMs, the outcome of treatment is not ideal in approximately 40%-50% of patients.
Only about 10% of patients can see the complete gap.
15 In addition, after 10 years of laser treatment, 35% of the cases were redarkened by CM.
In enlarged CMs, especially early
The treatment response may be worse at the beginning.
17 18 other lasers, such as Alexander or long pulse nd-in these cases-
The doped yttrium aluminum garnet laser may be more effective than the PDL 19 20, but the fat CMs remains a therapeutic challenge.
Therefore, an alternative treatment option is needed for CMs
Especially for the treatment of fat
Resistant to repeated CMs.
In this study, we hypothesize that the injection of boleyin combined with electropuncture (
Treatment of electrical hardening (EST))
This may be a viable and safe alternative treatment option for CMs.
Injection of boleyin (sclerotherapy)
It is usually used to treat vascular malformation of larger blood vessels (
Venous and lymphatic malformation).
According to the literature, this treatment is effective in about 80%-90% of patients.
21 22 Unfortunately, this therapy cannot be used in CMs because the vessel diameter is too small for local intra-vascular injections.
23 thus, the administration of borectin cannot be delivered to the endothelial cells with therapeutic hardening.
24. \"Electromigration\" is a physical phenomenon that causes changes in membrane structure by exposing cells to short and intense electric fields.
This modification of the cell membrane increases its permeability and allows molecules that normally do not pass through the cell membrane to be transported to the cell\'s internal environment.
Therefore, electric perforation is an ideal method of local administration, especially local administration, while avoiding systematic side effects.
EST is a combination of electric perforation and hardened drugs.
In this protocol, we will use the definition EST of an electropuncture combined with a local boleyin injection.
In EST, electroperforation will help to deliver boleyin to the endothelial cells of the abnormally developed capillary, resulting in local drug effects.
We assume that the hardening effect of boleyin will reach the endothelial, where it can cause vascular damage and eventually lead to the fading of CM.
In oncology, EST is also referred to as \"electrochemotherapy\" due to the cell toxicity of boleyin \".
EST is exactly the same as electrochemotherapy, but its name is different because it is intended to enhance the hardening effect of borecin rather than the toxicity effect.
Electrochemotherapy has been used in clinical practice around the world for a wide range of indications, from kelids to kapsi sarcoma.
Through a pilot study, we aim to explore whether it is possible for EST to become a new treatment for CMs.
This pilot study will not be a hypothesis test, but will provide us with preliminary information on the feasibility of such an intervention and will determine the changes required to design a larger hypothesis test Institute.
If we find preliminary evidence of the efficacy of EST, we will continue to investigate whether EST can be a valuable addition to CMs\'s current treatment guidelines.
Objective: to determine the feasibility and current research design of EST as a treatment plan for CMs.
Secondary objectives (s)
: To explore the effectiveness of EST as a treatment plan for CMs.
Explore the safety of EST as a CMs treatment regimen.
Many treatments have been used to treat CMs in the last century, such as ar laser, selective light heat treatment, and skin cooling
The results were disappointing.
14 out of 1985, pulse-dye laser (PDL)
Since then, the therapy has been considered national. of-the-
Art therapy model of CMs.
2 14 in laser treatment, abnormal blood vessels are photocoagulation when the covered skin is preserved.
Some other less widely accepted treatments, such as photodynamics therapy and intense pulse light, are described in the literature, but the evidence suggests that these treatments are below the gold standard of laser therapy.
2 Although PDL is the only widely accepted treatment option for CMs, the outcome of treatment is not ideal in approximately 40%-50% of patients.
Only about 10% of patients can see the complete gap.
15 In addition, after 10 years of laser treatment, 35% of the cases were redarkened by CM.
In enlarged CMs, especially early
The treatment response may be worse at the beginning.
17 18 other lasers, such as Alexander or long pulse nd-in these cases-
The doped yttrium aluminum garnet laser may be more effective than the PDL 19 20, but the fat CMs remains a therapeutic challenge.
Therefore, an alternative treatment option is needed for CMs
Especially for the treatment of fat
Resistant to repeated CMs.
In this study, we hypothesize that the injection of boleyin combined with electropuncture (
Treatment of electrical hardening (EST))
This may be a viable and safe alternative treatment option for CMs.
Injection of boleyin (sclerotherapy)
It is usually used to treat vascular malformation of larger blood vessels (
Venous and lymphatic malformation).
According to the literature, this treatment is effective in about 80%-90% of patients.
21 22 Unfortunately, this therapy cannot be used in CMs because the vessel diameter is too small for local intra-vascular injections.
23 thus, the administration of borectin cannot be delivered to the endothelial cells with therapeutic hardening.
24. \"Electromigration\" is a physical phenomenon that causes changes in membrane structure by exposing cells to short and intense electric fields.
This modification of the cell membrane increases its permeability and allows molecules that normally do not pass through the cell membrane to be transported to the cell\'s internal environment.
Therefore, electric perforation is an ideal method of local administration, especially local administration, while avoiding systematic side effects.
EST is a combination of electric perforation and hardened drugs.
In this protocol, we will use the definition EST of an electropuncture combined with a local boleyin injection.
In EST, electroperforation will help to deliver boleyin to the endothelial cells of the abnormally developed capillary, resulting in local drug effects.
We assume that the hardening effect of boleyin will reach the endothelial, where it can cause vascular damage and eventually lead to the fading of CM.
In oncology, EST is also referred to as \"electrochemotherapy\" due to the cell toxicity of boleyin \".
EST is exactly the same as electrochemotherapy, but its name is different because it is intended to enhance the hardening effect of borecin rather than the toxicity effect.
Electrochemotherapy has been used in clinical practice around the world for a wide range of indications, from kelids to kapsi sarcoma.
Through a pilot study, we aim to explore whether it is possible for EST to become a new treatment for CMs.
This pilot study will not be a hypothesis test, but will provide us with preliminary information on the feasibility of such an intervention and will determine the changes required to design a larger hypothesis test Institute.
If we find preliminary evidence of the efficacy of EST, we will continue to investigate whether EST can be a valuable addition to CMs\'s current treatment guidelines.
Objective: to determine the feasibility and current research design of EST as a treatment plan for CMs.
Secondary objectives (s)
: To explore the effectiveness of EST as a treatment plan for CMs.
Explore the safety of EST as a CMs treatment regimen.
Methods and analysis of forward-looking, random, internal design
Patient control in phase II trial study.
This is a single-center study of the Academic Medical Center (AMC)in Amsterdam.
In this study, we will include patients with fat CMs.
In each patient, we will randomly assign three different regions within the fat CM (A)EST, (B)
Alone or (C)no treatment.
Treatment results will be used about 7 weeks after the treatment procedure-
Report and doctor
Global Assessment scores, color studies, laser spot imaging, and adverse event reports reported.
Figure 1 shows a simplified learning flow chart.
Download figureOpen in the new tabDownload powerpoint figure 1, including the random process.
ROI of the area of interest.
In this study, patients with fat CMs were included.
The enlargement is defined as an increase in the thickness or ball of CM.
This can be found in about 20% of CMs.
All inclusion and exclusion criteria are listed in Table 1.
Patients visiting at the Dutch Institute of pigment disorders and the AMC dermatology, plastic surgery and reconstruction surgery clinic in Amsterdam, as well as members of the Dutch CMs patient organization and support group will be invited to attend.
Patients will be contacted by phone, email, email or social media to inform them about the study.
Investigators will assess eligibility for patients who are interested in participation.
When the patient is eligible to participate, detailed research information will be provided orally and in writing.
If the patient chooses to participate, an informed consent form must be signed under the witness of the members of the study team.
View this table: View the inline View pop-up table 1 inclusion and exclusion criteria since this pilot study is exploratory, one of the main objectives is to obtain information on conducting a larger trial of therapeutic efficacy.
As a result, a formal power or sample size calculation was not performed.
This pilot study is not a hypothesis test, nor does it propose an inference statistical analysis.
To explore the feasibility, effectiveness and safety of EST, our goal includes about 20 patients.
This number is determined by our research team based on the need to review the feasibility (
For example, the learning curve of the treating doctor)
Our current patient flow and budget constraints.
Random, treatment allocation, and blinking of the three regions of interest (ROIs)
About 1. 5×1.
5 cm with uniform appearance (
Based on fertilizer/ball and color)
An investigator will be appointed within CM.
These areas will be numbered ROI-1, ROI-2 and ROI-3.
An example of this process is shown in figure 2.
These ROIs will be randomly assigned (A)
Treated with EST ,(B)
Injection of boleyin or (C)no treatment.
The randomized goal was to ensure that the treating physician did not choose areas that were less serious than the control intervention for the study intervention.
Random will be based on a number-generated list created by random experts using ALEA software.
Combination of numbers and letters (eg, 1B–2A–3C)
Will appear on each patient in a random order.
Download the selection and numbering examples of the three homogeneous regions of interest in figure 2 in the new tabDownload powerpoint (ROIs)
In capillary malformation (
Image source: # & gid = 1 & pid = 14).
The patient will not be informed of the random results.
We will take steps to blind the patient to get the distribution of treatment for three ROIs.
All ROIs will be anesthesia and the patient will not be able to observe the course of treatment.
Only ROIs that receive boleyin and/or EST will be truly injected, and in ROI that is not treated, the injection will be simulated by a needle prick.
However, electropuncture surgery may be difficult to make the patient completely blind, as the patient may feel a pulse near the ROI treated with EST.
The treating doctor is not blind because it is impossible in practice.
The result assessor is an investigator who is not involved in the treatment procedure and he/she will turn a blind eye to ROIs\'s treatment allocation.
Interventional therapy will be performed in one treatment.
EST will use Cliniporator (
IGEA in Carpi, Italy).
Clinical doctor (model EPS02)is a CE-
Reversible electrical perforation certification device for tissue.
The handle with the electrode is attached to the device.
The electrodes are placed in the tissue to produce an electric field.
As shown in figure 3, two examples of electrodes.
In this study, plate electrodes are preferred because they do not penetrate the skin and are generally less harmful.
For deeper lesions, however, the option is to switch to the needle electrode.
In the ROI of the received EST, the electrical perforation of the tissue was combined with a local boleyin injection.
The dosage of boleyin was 0.
25 mg or unit/m3, according to the standard operating procedure for electrochemotherapy described previously by Mir et al.
The 30 mg effect of boleyin is equivalent to about 1 USP, 1 unit and 1000 international units (IU)
The latter is the most widely accepted measure in the world.
31 32 The second ROI will be treated with boleyin injection according to the same protocol, but no electropuncture will be applied.
The last ROI will not be processed.
Only these three ROIs are measured.
The remaining area of the CM that is not outside of ROIs will not be processed and will not be measured.
Since the security of EST is not clearly defined, we will not use EST to handle the entire CM.
In the future, when there is more evidence of the safety and efficacy of EST in the fat CMs, this therapy may be used to treat the entire CMs.
Download the new tabDownload powerpointFigure month (A)
Flat electrode. (B)
Hexagonal needle electrode.
The main result measurement currently does not measure the objective result measurement of the fat CMs, which measures the fat and color of the CM.
So we chose (change in)
The appearance measured by observers and patients is the main outcome measure of this study.
This is using the Global Change score assessment and the patient and observer scar assessment scale (POSAS)V. 2. 0.
The global assessment of post-treatment improvement is assessed separately by physicians and patients.
This global assessment score is a subjective measure that will only be evaluated after treatment by patients and outcome assessors.
There are five groups of global improvement: no improvement or deterioration (0% regression)
Small improvements (
> 0%-25% regression)
Moderate improvement (
> 25%-50% regression)
Significantly improved (
> 50%-75% regression)
Close to complete or complete relief (
> 75%-100% regression).
Both patients and doctors have chosen a category that best expresses the amount of regression.
POSAS is a reliable and effective subjective assessment scale consisting of two digital scales: patient scar assessment scale (patient scale)
And observer scar assessment scale (observer scale).
The observer scale included six parameters: Vascular formation, pigmentation, thickness, relief, flexibility and surface area.
The six parameters of the patient scale are: pain, itching, color, stiffness, thickness and irregular surface.
All items were scored on normal skin from 1 to 10 according to the Likert scale before and after treatment.
Since the POSAS scale was initially developed for scars, bleeding symptoms of CMs were not included in the questionnaire.
So, we added a question to the POSAS scale: \"In the last few weeks, does the bleeding from CM burden you? ’.
Secondary outcome measures adverse events all adverse events will be reported during follow-upup.
These will be classified according to the general Terminology Criteria for Adverse Events4. 0 guidelines.
Color difference in ROI in color CM, relative to the color of the normal skin on the opposite side, will be used in Hue (
Model CR-Minolta Color Meter300).
The Minolta Color Meter uses the L * a * B * color coordinate system where L * represents brightness, a * values from green to red, and B * values from blue to yellow.
The color difference between ROI and normal skin will be calculated using L * a * B * coordinates and represented by ΔE
ΔE will be determined before and after treatment according to the following equation (CIE76-formula): ΔE=((ΔL)2+(Δa)2+(Δb)2)1/2.
The low value of ΔE indicates small color difference or light centimeter, and the high value of ΔE indicates large color difference.
Contrast Imaging of laser scattered pattern (LSCI)
Is an optical imaging technique that will be used in this study to display perfusion in CMs ROIs.
Perfusion will be measured in perfusion units per second.
Feasibility results measurements we will report the feasibility aspects, including the feasibility of intervention techniques, applicability of POSAS scores in CM studies, random techniques, and blind method procedures.
We will record any problems that arise in these areas by interviewing patients, doctors and investigators.
In addition, recruitment and consent rates will be reported.
Study Procedure 1 patient features after signing the informed consent form (
Gender, age, previous treatment, location of CM and patient-
Symptoms reported)
Will be collected.
Depending on the fertilizer size and nodules and color, the researcher will select three uniform ROIs as described in the random process.
Injuries in the face, skin-covered joints or mucosal tissue will not be treated.
The outline of CM and three ROIs will be drawn to include ROI-numbers.
CM and three ROIs will be photographed.
Patients and doctors will complete the POSAS score for each of the three ROIs.
In addition, color and perfusion of the three ROIs will be measured using hue LSCI, respectively.
After baseline measurements, ROIs will be randomly assigned (A)EST, (B)
Alone or (C)no treatment.
ROIs to be treated will use nerve block anesthesia with 2%.
After that, then by injection of boleyin0.
25 mg or unit/cubic meter)
, The ROI that was randomly assigned to EST will be treated with a pulse using Cliniporator within 10 minutes of the boleyin injection.
The treatment procedure will be carried out in the clinic.
After 24-48 hours, the researcher calls the patient to check for pain, swelling, wound healing.
If there are shocking symptoms, patients will be invited to the clinic.
Visit 2 after 1 week±3 days)
The patient will go to the clinic for wound examination.
ROIs will be photographed and any adverse events will be registered in the electronic patient file and the research file.
In the third visit after 7 ± 1 week, primary and secondary results will be measured (
Global Assessment of POSAS, LSCI and color studies)
Follow the same procedure as the baseline measurement for access 1.
Adverse events will be registered.
During the last visit, the patient and the doctor will discuss whether the patient has further treatment needs.
Table 2 shows a schematic diagram of all accesses.
View this table: View inline View pop-up table 2 Schematic diagram of research programs and measurements for each studyGCP)
Database management will use approved software.
A separate, qualified data monitor will provide GCP data monitoring.
PlanData will be analyzed based on protocol analysis data.
Since this study is exploratory and focuses primarily on the feasibility of research design and procedures, we will use descriptive statistics mainly in combination with qualitative data.
The classified data will be expressed as numbers (n)
And percentage (%)
, Will use the average and SD (
Normal distribution of data
Or with median and IQRs (non-
Parameter data).
Exploratory comparison for treatment allocation group and
Pretreatment and post-treatment of patient results
Treatment, we will also use (non-parametric)
Statistics are made based on the pairing structure of the data.
However, we will explain these results cautiously, as we are aware that our study does not have sufficient capacity to formally examine the efficacy hypothesis.
95% CIs will express statistical uncertainty.
Prospective Randomized Trial Design
Patient control in phase II trial study.
This is a single-center study of the Academic Medical Center (AMC)in Amsterdam.
In this study, we will include patients with fat CMs.
In each patient, we will randomly assign three different regions within the fat CM (A)EST, (B)
Alone or (C)no treatment.
Treatment results will be used about 7 weeks after the treatment procedure-
Report and doctor
Global Assessment scores, color studies, laser spot imaging, and adverse event reports reported.
Figure 1 shows a simplified learning flow chart.
Download figureOpen in the new tabDownload powerpoint figure 1, including the random process.
ROI of the area of interest.
In this study, patients with fat CMs were included.
The enlargement is defined as an increase in the thickness or ball of CM.
This can be found in about 20% of CMs.
All inclusion and exclusion criteria are listed in Table 1.
Patients visiting at the Dutch Institute of pigment disorders and the AMC dermatology, plastic surgery and reconstruction surgery clinic in Amsterdam, as well as members of the Dutch CMs patient organization and support group will be invited to attend.
Patients will be contacted by phone, email, email or social media to inform them about the study.
Investigators will assess eligibility for patients who are interested in participation.
When the patient is eligible to participate, detailed research information will be provided orally and in writing.
If the patient chooses to participate, an informed consent form must be signed under the witness of the members of the study team.
View this table: View the inline View pop-up table 1 inclusion and exclusion criteria since this pilot study is exploratory, one of the main objectives is to obtain information on conducting a larger trial of therapeutic efficacy.
As a result, a formal power or sample size calculation was not performed.
This pilot study is not a hypothesis test, nor does it propose an inference statistical analysis.
To explore the feasibility, effectiveness and safety of EST, our goal includes about 20 patients.
This number is determined by our research team based on the need to review the feasibility (
For example, the learning curve of the treating doctor)
Our current patient flow and budget constraints.
Random, treatment allocation, and blinking of the three regions of interest (ROIs)
About 1. 5×1.
5 cm with uniform appearance (
Based on fertilizer/ball and color)
An investigator will be appointed within CM.
These areas will be numbered ROI-1, ROI-2 and ROI-3.
An example of this process is shown in figure 2.
These ROIs will be randomly assigned (A)
Treated with EST ,(B)
Injection of boleyin or (C)no treatment.
The randomized goal was to ensure that the treating physician did not choose areas that were less serious than the control intervention for the study intervention.
Random will be based on a number-generated list created by random experts using ALEA software.
Combination of numbers and letters (eg, 1B–2A–3C)
Will appear on each patient in a random order.
Download the selection and numbering examples of the three homogeneous regions of interest in figure 2 in the new tabDownload powerpoint (ROIs)
In capillary malformation (
Image source: # & gid = 1 & pid = 14).
The patient will not be informed of the random results.
We will take steps to blind the patient to get the distribution of treatment for three ROIs.
All ROIs will be anesthesia and the patient will not be able to observe the course of treatment.
Only ROIs that receive boleyin and/or EST will be truly injected, and in ROI that is not treated, the injection will be simulated by a needle prick.
However, electropuncture surgery may be difficult to make the patient completely blind, as the patient may feel a pulse near the ROI treated with EST.
The treating doctor is not blind because it is impossible in practice.
The result assessor is an investigator who is not involved in the treatment procedure and he/she will turn a blind eye to ROIs\'s treatment allocation.
Interventional therapy will be performed in one treatment.
EST will use Cliniporator (
IGEA in Carpi, Italy).
Clinical doctor (model EPS02)is a CE-
Reversible electrical perforation certification device for tissue.
The handle with the electrode is attached to the device.
The electrodes are placed in the tissue to produce an electric field.
As shown in figure 3, two examples of electrodes.
In this study, plate electrodes are preferred because they do not penetrate the skin and are generally less harmful.
For deeper lesions, however, the option is to switch to the needle electrode.
In the ROI of the received EST, the electrical perforation of the tissue was combined with a local boleyin injection.
The dosage of boleyin was 0.
25 mg or unit/m3, according to the standard operating procedure for electrochemotherapy described previously by Mir et al.
The 30 mg effect of boleyin is equivalent to about 1 USP, 1 unit and 1000 international units (IU)
The latter is the most widely accepted measure in the world.
31 32 The second ROI will be treated with boleyin injection according to the same protocol, but no electropuncture will be applied.
The last ROI will not be processed.
Only these three ROIs are measured.
The remaining area of the CM that is not outside of ROIs will not be processed and will not be measured.
Since the security of EST is not clearly defined, we will not use EST to handle the entire CM.
In the future, when there is more evidence of the safety and efficacy of EST in the fat CMs, this therapy may be used to treat the entire CMs.
Download the new tabDownload powerpointFigure month (A)
Flat electrode. (B)
Hexagonal needle electrode.
The main result measurement currently does not measure the objective result measurement of the fat CMs, which measures the fat and color of the CM.
So we chose (change in)
The appearance measured by observers and patients is the main outcome measure of this study.
This is using the Global Change score assessment and the patient and observer scar assessment scale (POSAS)V. 2. 0.
The global assessment of post-treatment improvement is assessed separately by physicians and patients.
This global assessment score is a subjective measure that will only be evaluated after treatment by patients and outcome assessors.
There are five groups of global improvement: no improvement or deterioration (0% regression)
Small improvements (
> 0%-25% regression)
Moderate improvement (
> 25%-50% regression)
Significantly improved (
> 50%-75% regression)
Close to complete or complete relief (
> 75%-100% regression).
Both patients and doctors have chosen a category that best expresses the amount of regression.
POSAS is a reliable and effective subjective assessment scale consisting of two digital scales: patient scar assessment scale (patient scale)
And observer scar assessment scale (observer scale).
The observer scale included six parameters: Vascular formation, pigmentation, thickness, relief, flexibility and surface area.
The six parameters of the patient scale are: pain, itching, color, stiffness, thickness and irregular surface.
All items were scored on normal skin from 1 to 10 according to the Likert scale before and after treatment.
Since the POSAS scale was initially developed for scars, bleeding symptoms of CMs were not included in the questionnaire.
So, we added a question to the POSAS scale: \"In the last few weeks, does the bleeding from CM burden you? ’.
Secondary outcome measures adverse events all adverse events will be reported during follow-upup.
These will be classified according to the general Terminology Criteria for Adverse Events4. 0 guidelines.
Color difference in ROI in color CM, relative to the color of the normal skin on the opposite side, will be used in Hue (
Model CR-Minolta Color Meter300).
The Minolta Color Meter uses the L * a * B * color coordinate system where L * represents brightness, a * values from green to red, and B * values from blue to yellow.
The color difference between ROI and normal skin will be calculated using L * a * B * coordinates and represented by ΔE
ΔE will be determined before and after treatment according to the following equation (CIE76-formula): ΔE=((ΔL)2+(Δa)2+(Δb)2)1/2.
The low value of ΔE indicates small color difference or light centimeter, and the high value of ΔE indicates large color difference.
Contrast Imaging of laser scattered pattern (LSCI)
Is an optical imaging technique that will be used in this study to display perfusion in CMs ROIs.
Perfusion will be measured in perfusion units per second.
All adverse events will be reported in the follow-up periodup.
These will be classified according to the general Terminology Criteria for Adverse Events4. 0 guidelines.
Color difference in ROI in color CM, relative to the color of the normal skin on the opposite side, will be used in Hue (
Model CR-Minolta Color Meter300).
The Minolta Color Meter uses the L * a * B * color coordinate system where L * represents brightness, a * values from green to red, and B * values from blue to yellow.
The color difference between ROI and normal skin will be calculated using L * a * B * coordinates and represented by ΔE
ΔE will be determined before and after treatment according to the following equation (CIE76-formula): ΔE=((ΔL)2+(Δa)2+(Δb)2)1/2.
The low value of ΔE indicates small color difference or light centimeter, and the high value of ΔE indicates large color difference.
Contrast Imaging of laser scattered pattern (LSCI)
Is an optical imaging technique that will be used in this study to display perfusion in CMs ROIs.
Perfusion will be measured in perfusion units per second.
Feasibility results measurements we will report the feasibility aspects, including the feasibility of intervention techniques, applicability of POSAS scores in CM studies, random techniques, and blind method procedures.
We will record any problems that arise in these areas by interviewing patients, doctors and investigators.
In addition, recruitment and consent rates will be reported.
Study Procedure 1 patient features after signing the informed consent form (
Gender, age, previous treatment, location of CM and patient-
Symptoms reported)
Will be collected.
Depending on the fertilizer size and nodules and color, the researcher will select three uniform ROIs as described in the random process.
Injuries in the face, skin-covered joints or mucosal tissue will not be treated.
The outline of CM and three ROIs will be drawn to include ROI-numbers.
CM and three ROIs will be photographed.
Patients and doctors will complete the POSAS score for each of the three ROIs.
In addition, color and perfusion of the three ROIs will be measured using hue LSCI, respectively.
After baseline measurements, ROIs will be randomly assigned (A)EST, (B)
Alone or (C)no treatment.
ROIs to be treated will use nerve block anesthesia with 2%.
After that, then by injection of boleyin0.
25 mg or unit/cubic meter)
, The ROI that was randomly assigned to EST will be treated with a pulse using Cliniporator within 10 minutes of the boleyin injection.
The treatment procedure will be carried out in the clinic.
After 24-48 hours, the researcher calls the patient to check for pain, swelling, wound healing.
If there are shocking symptoms, patients will be invited to the clinic.
Visit 2 after 1 week±3 days)
The patient will go to the clinic for wound examination.
ROIs will be photographed and any adverse events will be registered in the electronic patient file and the research file.
In the third visit after 7 ± 1 week, primary and secondary results will be measured (
Global Assessment of POSAS, LSCI and color studies)
Follow the same procedure as the baseline measurement for access 1.
Adverse events will be registered.
During the last visit, the patient and the doctor will discuss whether the patient has further treatment needs.
Table 2 shows a schematic diagram of all accesses.
Look here: After checking the monthly visitVisit study patient informed consent form of the inlineView popupTable monthly outline learning process and measurement, the patient line (
Gender, age, previous treatment, location of CM and patient-
Symptoms reported)
Will be collected.
Depending on the fertilizer size and nodules and color, the researcher will select three uniform ROIs as described in the random process.
Injuries in the face, skin-covered joints or mucosal tissue will not be treated.
The outline of CM and three ROIs will be drawn to include ROI-numbers.
CM and three ROIs will be photographed.
Patients and doctors will complete the POSAS score for each of the three ROIs.
In addition, color and perfusion of the three ROIs will be measured using hue LSCI, respectively.
After baseline measurements, ROIs will be randomly assigned (A)EST, (B)
Alone or (C)no treatment.
ROIs to be treated will use nerve block anesthesia with 2%.
After that, then by injection of boleyin0.
25 mg or unit/cubic meter)
, The ROI that was randomly assigned to EST will be treated with a pulse using Cliniporator within 10 minutes of the boleyin injection.
The treatment procedure will be carried out in the clinic.
After 24-48 hours, the researcher calls the patient to check for pain, swelling, wound healing.
If there are shocking symptoms, patients will be invited to the clinic.
Visit 2 after 1 week±3 days)
The patient will go to the clinic for wound examination.
ROIs will be photographed and any adverse events will be registered in the electronic patient file and the research file.
In the third visit after 7 ± 1 week, primary and secondary results will be measured (
Global Assessment of POSAS, LSCI and color studies)
Follow the same procedure as the baseline measurement for access 1.
Adverse events will be registered.
During the last visit, the patient and the doctor will discuss whether the patient has further treatment needs.
Table 2 shows a schematic diagram of all accesses.
View this table: View inline View pop-up table 2 Schematic diagram of research programs and measurements for each studyGCP)
Database management will use approved software.
A separate, qualified data monitor will provide GCP data monitoring.
PlanData will be analyzed based on protocol analysis data.
Since this study is exploratory and focuses primarily on the feasibility of research design and procedures, we will use descriptive statistics mainly in combination with qualitative data.
The classified data will be expressed as numbers (n)
And percentage (%)
, Will use the average and SD (
Normal distribution of data
Or with median and IQRs (non-
Parameter data).
Exploratory comparison for treatment allocation group and
Pretreatment and post-treatment of patient results
Treatment, we will also use (non-parametric)
Statistics are made based on the pairing structure of the data.
However, we will explain these results cautiously, as we are aware that our study does not have sufficient capacity to formally examine the efficacy hypothesis.
95% CIs will express statistical uncertainty.
All data is processed in a confidential manner.
Only the investigators listed in this agreement can access the source data.
No identifiable information is entered in the database.
The topic identification code list is used to link data in the database to the topic.
The subject recognition code is not based on the initial or date of birth of the patient\'s name.
The key to the code is maintained by the investigator (SERH)
In the password encryption file.
The processing of personal data in this study conforms to the Dutch personal data protection law (
In the Netherlands: Persoonsgegevens, De Wet bersheming).
Data Security Commission (data security commission)DSMB)
It is established for continuous security monitoring and medium-term analysis of security data.
This is an independent committee consisting of a urologist familiar with the subject matter of the study and a statistician/epidemiology.
Members of this DSMB did not participate in this study, nor did they conflict of interest with research sponsors.
In short, the task and responsibility of DSMB is to monitor security data when 50% of patients (n=10)
Has been randomly assigned and security can be monitored temporarily if needed.
Any mortality will be reported directly to DSMB and the cause of death and possible trials will be evaluated-related (serious)adverse events.
The reason for the proposed termination of the study to clear the injury will be based on a significant increase (serious)
Adverse events, special attention to the occurrence of serious local events (
Skin necrosis or severe ulcer, nerve damage, severe bleeding or any other complications requiring surgical intervention).
Statistical stop boundaries are not set in advance.
In the mid-term analysis, DSMB will also assess the overall conduct of the trial in terms of protocol compliance, recruitment, follow-up losses, etc.
Integrity of data and reports for independent data monitors.
Communication research results will be published in the peer
It will be published at the International Conference.
In addition, the results of the study will be fed back to the patient group through news on the website and social media.
The study was not funded by public, commercial or non-commercial funding agenciesfor-profit sectors.
All data is kept confidential.
Only the investigators listed in this agreement can access the source data.
No identifiable information is entered in the database.
The topic identification code list is used to link data in the database to the topic.
The subject recognition code is not based on the initial or date of birth of the patient\'s name.
The key to the code is maintained by the investigator (SERH)
In the password encryption file.
The processing of personal data in this study conforms to the Dutch personal data protection law (
In the Netherlands: Persoonsgegevens, De Wet bersheming).
Data Security Commission (data security commission)DSMB)
It is established for continuous security monitoring and medium-term analysis of security data.
This is an independent committee consisting of a urologist familiar with the subject matter of the study and a statistician/epidemiology.
Members of this DSMB did not participate in this study, nor did they conflict of interest with research sponsors.
In short, the task and responsibility of DSMB is to monitor security data when 50% of patients (n=10)
Has been randomly assigned and security can be monitored temporarily if needed.
Any mortality will be reported directly to DSMB and the cause of death and possible trials will be evaluated-related (serious)adverse events.
The reason for the proposed termination of the study to clear the injury will be based on a significant increase (serious)
Adverse events, special attention to the occurrence of serious local events (
Skin necrosis or severe ulcer, nerve damage, severe bleeding or any other complications requiring surgical intervention).
Statistical stop boundaries are not set in advance.
In the mid-term analysis, DSMB will also assess the overall conduct of the trial in terms of protocol compliance, recruitment, follow-up losses, etc.
Integrity of data and reports for independent data monitors.
Communication research results will be published in the peer
It will be published at the International Conference.
In addition, the results of the study will be fed back to the patient group through news on the website and social media.
The study was not funded by public, commercial or non-commercial funding agenciesfor-profit sectors.
In this pilot study, we will explore the potential of EST as a new treatment model for CMs.
A new mode of treatment will benefit many CMs patients, especially those with obesity, for treatment
Conventional laser therapy is not feasible for drug resistance and recurrent CMs.
This pilot study is an important first step in finding alternative treatment options for these patients.
Although EST has never been used in the treatment of fat CMs before, in other skin lesions, its working mechanism and therapeutic effect have pre-clinical and clinical evidence.
The working mechanism of EST is considered to be the synergistic effect of electro-perforation and boleyin.
The local effect of boleyin is enhanced because of the possibility of an increase in the concentration of low-permeability drugs in the cell by electrical perforation
A maximum of 10 tens of 000 times for boleyin.
More than 25. 26 pre-clinical studies have shown that the effect of EST on nodule-like skin lesions is mainly due to vascular interference on the supply vessels of the lesions.
34-36 in the pre-clinical study of mouse fibrotumor cells by Sersa et al, immediate vascular disruption effects of chemotherapy leading to decreased tumor blood flow, hypoxia and reduced tumor oxidation were found.
In addition, the endothelial cells of the tumor vessels appear to be exposed to an electric field of about 40% kbps than the surrounding tumor cells.
Subsequent endothelial swelling and apoptosis lead to delayed vascular disruption effect of tumor necrosis, long-term reduction of tumor blood flow, and finally tumor regression.
This phenomenon (
Vascular damage, reduced blood flow, regression of lesions)
It is also the expected effect of CMs treatment.
Clinically, EST has been used for many skin lesions ranging from melanoma to basal cell carcinoma with an objective effective rate of 69. 7% to 100%.
38. it has recently been suggested to use it as a new \"standard of care\" for the kapossi muscle Festival, a vascular-based tumor, Since 75% of patients
26. In a study in Manca et al28, 20 patients were treated with EST, of which 35 were kelids and fat scars, scar height, scar volume, erythema and
The current pilot study must determine whether EST can also effectively reduce both fat and erythema in CMs.
No serious adverse events were reported in the literature regarding EST treatment of other skin or subcutaneous lesions.
The most common complications are transient pain, erythema, or other local skin toxicity, pigmentation, and fever.
26 39. in the comments of Testori et al, 40 authors mentioned that due to EST immutability collage of the extracellular matrix and proteins, the post-treatment injury healed without scars, unlike other Physical ablation techniques.
In this feasibility trial, the safety and efficacy of EST as a treatment option for fat CMs will be explored.
When the results of this study provide preliminary evidence of the safety and effectiveness of EST in the fat CMs, a larger range of hypothesis test trials will be conducted.
The authors thank Rob de Haan, Michal Heger and Sanne Jansen for their valuable comments on the research programme. References1.
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Xopenurlcrossrefpmedfootnotescontriators SERH, AW, CMAMH participated in the research established.
The study was conceived and designed by SERH, AW, DMB and CMAMH.
Data will be collected by SERH, AW and CMAMH.
SERH, AW, DMB and CMAMH will perform data analysis or interpretation of the data.
SERH drafted a preliminary manuscript of the research programme.
AW, DMB and CMAMH modified the intellectual content of the manuscript and approved the final manuscript submitted.
The funding for this work was supported by individual academic research scholarships obtained by the corresponding author SERH. IGEA S. p. A.
The materials required for this institute are provided free of charge.
No one declared a competitive interest.
The Institutional Review Committee of the Amsterdam Academic Medical Center approved the research program (V1.
October 25, 2016).
Uncommissioned source and peer review;
External peer review.