[Rapamycin and HPPH Co-Loaded Nanodrug Delivered via Dissolvable Microneedles to Treat Port-Wine Stains]. / å ±è½½é›·å¸•éœ‰ç´ å’Œå ‰å ‹æ´›çš„çº³ç±³è¯ç‰©å¤åˆå¯æº¶è§£å¾®é’ˆæ²»ç–—é²œçº¢æ–‘ç—£çš„å®žéªŒç ”ç©¶.

Objective: Port-wine stains are a kind of dermatological disease of congenital capillary malformation. Based on the biological characteristics of port-wine stains and the advantages of microneedle transdermal administration, we intend to construct a nanodrug co-loaded with rapamycin (RPM), an anti-angiogenesis drug, and photochlor (HPPH), a photosensitizer, and integrate the nanodrug with dissolvable microneedles (MN) to achieve anti-angiogenesis and photodynamic combination therapy for port-wine stains. Methods: First, RPM and HPPH co-loaded nanoparticles (RPM-HPPH NP) were prepared by the emulsification solvent-volatilization method, and its ability to generate reactive oxygen species (ROS) was investigated under 660 nm laser irradiation. Mouse hemangioendothelioma endothelial cells (EOMA) were used as the subjects of the study. The cellular uptake behaviors were examined by fluorescence microscopy and flow cytometry. The cytotoxicity effects of RPM-HPPH NP with or without 660 nm laser irradiation on EOMA cells were examined by MTT assays (with free RPM serving as the control). Then, hyaluronic acid (HA) dissolvable microneedles loaded with RPM-HPPH NP (RPM-HPPH NP@HA MN) were obtained by compounding the nanodrug with HA dissolvable microneedle system through the molding method. The morphological characteristics and mechanical properties of RPM-HPPH NP@HA MN were investigated by scanning electron microscope and electronic universal testing machine. The penetration ability of RPM-HPPH NP@HA MN on the skin of nude mice was evaluated by trypan blue staining and H&E staining experiment. Results: The RPM-HPPH NP prepared in the study had a particle size of 150 nm and generated large amounts of ROS under laser irradiation. At the cellular level, RPM-HPPH NP was taken up by EOMA cells in a time-dependent manner. The cytotoxicity of RPM-HPPH NP was higher than that of free RPM with or without laser irradiation. Under laser irradiation, RPM-HPPH NP exhibited stronger cytotoxic effects and the difference was statistically significant (P<0.05). The height of the needle tip of RPM-HPPH NP@HA MN was 600 µm and the mechanical property of a single needle was 0.75048 N. Trypan blue staining and HE staining showed that pressing on the microneedles could produce pores on the skin surface and penetration of the stratum corneum. Conclusion: RPM-HPPH NP@HA MN can deliver RPM-HPPH NP percutaneously to the lesion tissue and realize the synergistic treatment of port-wine stains with anti-angiogenic therapy and photodynamic therapy, providing a new strategy for the construction of nanodrug-loaded microneedle delivery system and the clinical treatment of port-wine stains.

Current clinical evidence is insufficient to support HMME-PDT as the first choice of treatment for young children with port wine birthmarks.

BACKGROUND: Port wine birthmark (PWB) is a congenital vascular malformation of the skin. Pulsed dye laser (PDL) is the "gold standard" for the treatment of PWB globally. Hematoporphyrin monomethyl ether (HMME or hemoporfin)-mediated photodynamic therapy (HMME-PDT) has emerged as the first choice for PWB treatment, particularly for young children, in many major hospitals in China during the past several decades. AIM: To evaluate whether HMME-PDT is superior to PDL by comparing the clinical efficacies of both modalities. METHOD: PubMed records were searched for all relevant studies of PWB treatment using PDL (1988-2023) or HMME-PDT (2007-2023). Patient characteristics and clinical efficacies were extracted. Studies with a quartile percentage clearance or similar scale were included. A mean color clearance index (CI) per study was calculated and compared among groups. An overall CI (C0), with data weighted by cohort size, was used to evaluate the final efficacy for each modality. RESULT: A total of 18 HMME-PDT studies with 3910 patients in China were eligible for inclusion in this analysis. Similarly, 40 PDL studies with 5094 patients from nine different countries were eligible for inclusion in this analysis. Over 58% of patients in the HMME-PDT studies were minors (<18 years old). A significant portion (21.3%) were young children (<3 years old). Similarly, 33.2% of patients in the PDL studies were minors. A small proportion (9.3%) was young children. The overall clearance rates for PDL were slightly, but not significantly, higher than those for HMME-PDT in cohorts with patients of all ages (C0, 0.54 vs. 0.48, p = 0.733), subpopulations with only minors (C0, 0.54 vs. 0.46, p = 0.714), and young children (C0, 0.67 vs. 0.50, p = 0.081). Regrettably, there was a lack of long-term data on follow-up evaluations for efficacy and impact of HMME-PDT on young children in general, and central nervous system development in particular, because their blood-brain barriers have a greater permeability as compared to adults. CONCLUSION: PDL shows overall albeit insignificantly higher clearance rates than HMME-PDT in patients of all ages; particularly statistical significance is nearly achieved in young children. Collectively, current evidence is insufficient to support HMME-PDT as the first choice of treatment of PWBs in young children given: (1) overall inferior efficacy as compared to PDL; (2) risk of off-target exposure to meningeal vasculature during the procedure; (3) administration of steriods for mitigation of side effects; -and (4) lack of long-term data on the potential impact of HMME on central nervous system development in young children.

Klippel-Trenaunay syndrome or not? An exploration of atypical presentations.

Klippel-Trenaunay syndrome (KTS) is a rare, congenital disorder typically emerging in early infancy or childhood. The classic presentation of KTS is distinguished by a triad of clinical features: a port-wine stain, early-onset varicosities and limb overgrowth. However, a notable variant of KTS has been documented, characterised by limb shortening rather than lengthening, occasionally referred to as 'inverse KTS'. This report details two cases that display this unusual presentation-both patients had classical features of port-wine stain and varicose veins but both experienced shortening of the affected limb. Whether these cases represent a variant of KTS or a new clinical syndrome altogether is uncertain. They however offer valuable insights into the nuances and breadth of clinical manifestations associated with this syndrome.

Macrocheilia as an Atypical Clinical Presentation of Capillary Malformation-Arteriovenous Malformation Type 2.

This case report describes a 53-year-old man with multiple erythematous macules and papules diffusely distributed on the frontal area, cheeks, eyelids, nose, and supralabial skin.

Incidence of and Risk Factors for Fellow-Eye Involvement in Sturge-Weber Syndrome Children With Unilateral Glaucoma.

PRCIS: Among children with unilateral glaucoma associated with Sturge-Weber syndrome (SWS), 7 of 47 demonstrated involvement in the fellow eye, and that group had had earlier first-eye surgery relative to the noninvolvement group. PURPOSE: The aim of this study was to determine the incidence of and risk factors for fellow-eye involvement in children with unilateral SWS-associated glaucoma. MATERIALS AND METHODS: Children diagnosed with a unilateral facial port-wine stain and ipsilateral glaucoma before the age of 5 and followed up for at least 5 years were enrolled. The incidence rates of fellow-eye glaucoma involvement were estimated per 100 person-years, and factors associated with a higher incidence of fellow-eye involvement were investigated. RESULTS: A total of 47 children [24 (51.1%) girls] with unilateral SWS-associated glaucoma were included. All of them had facial port-wine stain involving ophthalmic division of the trigeminal nerve, and 18 (38.3%) had neurological comorbidities. The mean age at glaucoma diagnosis was 0.8±1.2 years [range, 0.08 (1 mo)-4.0 y]. Over a median follow-up of 8.4 years, glaucoma was diagnosed in the fellow eye of 7 of the children (14.9%; incidence rate of 1.8 per 100 person-years), 6 of whom were girls ( P =0.097) and 5 of whom were diagnosed before the age of 4 years ( P =0.508). The fellow-eye-involvement group showed significantly higher mean follow-up intraocular pressure in the fellow eye, older age at first-eye surgery (both P <0.005), and higher frequency of choroidal hemangioma both at first onset and in fellow eyes ( P =0.026 and 0.019, respectively). CONCLUSIONS: In this cohort of SWS children diagnosed with unilateral glaucoma, the risk of fellow-eye involvement was higher in girls, within the first 4 years, and in cases with choroidal hemangioma. The fellow-eye-involved children underwent surgery on the first eye earlier than those without fellow-eye involvement.

Delayed ulceration following combination pulse dye laser and topical sirolimus treatment for port wine birthmarks: A case series.

Port wine birthmarks (PWB) are capillary vascular malformations within the papillary and reticular dermis, most commonly occurring on the head and neck and may darken and thicken with age. Pulsed dye laser (PDL) is the gold standard of treatment for PWB as it selectively targets involved vessels. Sirolimus is a macrolide antibiotic that selectively inhibits mammalian target of rapamycin, thereby suppressing the angiogenesis pathways that can be activated by PDL. Sirolimus and PDL may be used together to treat PWB. We present a case series describing three cases of delayed ulceration and systemic sirolimus absorption following combination therapy, highlighting a potential complication and patient safety concern.

Pulsed dye laser and adjuvant topical therapies for the treatment of port-wine stains: A systematic review.

OBJECTIVES: The current gold standard treatment for port-wine stains (PWS) is pulsed dye laser (PDL). However, multiple treatment sessions may be necessary and complete resolution is often not achieved. Neoangiogenesis can occur soon after treatment and is thought to be a major factor contributing to treatment failure. Adjuvant antiangiogenic topical therapies may therefore improve the efficacy of pulsed dye laser treatment of port-wine stains. MATERIAL AND METHODS: Following PRISMA guidelines, we searched PubMed, Embase, Web of Science, and clinicaltrials.gov using "port-wine stain," "nevus flammeus," "capillary malformation," "sturge weber," and "pulsed dye laser" as keywords and medical subject heading (MeSH) terms. Articles were included if they (1) were a randomized controlled trial (RCT); (2) studied patients with PWS; and (3) investigated topical adjuvant therapies with PDL. Bias was assessed using the Critical Appraisal Skills Programme (CASP) Randomized Controlled Trial Standard Checklist. RESULTS: 1835 studies were identified, with six studies meeting inclusion criteria. The total number of patients studied was 103 (range: 9-23), with 8-36 week follow-up. The average age ranged from 11 to 33.5 years old. Three studies examined adjuvant topical sirolimus (n = 52), two examined timolol (n = 29), and one studied imiquimod (n = 22). Two of three RCTs reported no improvement through colorimetric analysis with topical sirolimus; however, one of these studies did show a significant improvement through Investigator Global Assessment (IGA) score. The last sirolimus study showed significant improvement through digital photographic image scoring (DPIA). Studies examining topical timolol reported no change in PWS appearance compared to placebo. The addition of 5% adjuvant imiquimod cream did lead to significant improvement. A variety of outcome measures were used. Imiquimod and sirolimus led to mild cutaneous adverse events, while timolol caused no side effects. None of the adverse events led to treatment discontinuation. Study quality was moderate in three, high in two, and low in one. CONCLUSION: The efficacy of adjuvant topical therapy was unclear. Limitations included variation in concentration and duration of adjuvant therapies, differences in follow-up time, and inconsistent outcome measure reporting. Given their potential clinical promise, larger prospective studies examining topical adjuvant therapies should be considered.

Hypothalamic-pituitary dysfunction in Sturge-Weber syndrome: case report and review of the literature.

OBJECTIVES: Sturge-Weber syndrome (SWS) is a rare neurocutaneous disorder that is characterized by a segmental dermatomal facial port-wine stain birthmark and is frequently accompanied by ipsilateral brain and eye abnormalities. We present a case of a patient with SWS who exhibited hypogonadotropic hypogonadism, growth hormone (GH) deficiency, and central hypothyroidism at the age of 20 despite the absence of radiographic findings in the pituitary and hypothalamus. CASE PRESENTATION: A 20-year-old male with SWS with epilepsy and Klippel-Trenaunay syndrome presents with delayed pubertal development, short stature, and obesity. Upon further examination, he was found to have biochemical and clinical evidence of hypogonadism, hypothyroidism, and GH deficiency. A pituitary MRI displayed no abnormalities of the pituitary or hypothalamus. Treatment with testosterone cypionate and levothyroxine was initiated. Despite successful pubertal induction, IGF-1 levels have remained low and treatment with recombinant human growth hormone (rhGH) is now being considered for metabolic benefits. CONCLUSIONS: This case emphasizes the importance of endocrine evaluation and treatment of hormonal deficiencies in patients with SWS despite the absence of radiographic findings.

Efficacy and influential factors of hematoporphyrin monomethyl ether mediated photodynamic therapy in the treatment for port-wine stains.

BACKGROUNDS: Hematoporphyrin monomethyl ether mediated photodynamic therapy (HMME-PDT) has emerged as an alternative approach for port-wine stain (PWS), which was primarily treated with pulsed dye laser (PDL). This study was aimed to evaluate the efficacy and safety of HMME-PDT for PWS and to explore influential factors on the efficacy. METHODS: A total of 254 patients were enrolled. Patients received an intravenous injection of HMME at 5 mg/kg. Lesion areas were irradiated with 532-nm light for 20-25 min. Efficacy was assessed according to fading of lesions and graded as excellent (≥90 %), good (60 %-89 %), fair (20 %-59 %), or poor (<20 %). Adverse events were recorded. Clinical data were analyzed including gender, age, lesion sub-type, lesion location and number of treatments. RESULTS: Overall, 72.4 % of patients achieved an effective response, with 27.6% showing excellent efficacy, 24.8 % showing good efficacy and 20.1 % showing fair efficacy. Only 27.6 % showed poor efficacy. Patients under the age of 18 obtained a better efficacy than adults. Lesions in face showed a better therapeutic outcome than those in neck or trunk and extremities. A more effective response was seen in pink type compared with nodular thickening type. Multiple HMME-PDT treatments could improve the clinical response. Lesion location, lesion sub-type, number of treatments were independent influential factors on efficacy. Adverse events included edema, blister, crust, hypopigmentation, hyperpigmentation, pain, itch and burning sensation. No severe systemic side events were observed. CONCLUSIONS: HMME-PDT was effective for treating PWS and was safe and well-tolerated by patients. It is worth further investigation in efficacy and safety involving more patients from medical institutions in different regions in China. The optimal treatment parameters and treatment protocols are still being explored in the clinical treatment for PWS.

Complication rates and safety of pulsed dye laser treatment for port-wine stain: a systematic review and meta-analysis.

Pulsed dye laser (PDL) is the most commonly used method for port-wine stain (PWS); however, no studies have reported the safety of PDL. This review aimed to collect and summarize complications reported in relevant literature, assess complication rates in treating PWS with PDL, and explore the relevant influencing factors. A systematic review and meta-analysis were conducted to search for related studies in PubMed, Embase, and the Cochrane Library until August 2022. Two reviewers independently evaluated the risk of bias of included studies. Stata Software version 17.0 was used for the analysis. All complications reported in the literature are divided into acute phase complications and long-term complications. Overall pooled purpura, edema, crusting, blistering, hyperpigmentation, hypopigmentation, and scarring rates were 98.3%, 97.6%, 21.5%, 8.7%, 12.8%, 0.9%, and 0.2%, respectively. Although the acute adverse reactions were found to be common, the long-term permanent complications clearly have a lower frequency, and the occurrence of scarring is much lower than that initially thought. This indicates that effective protective measures after treatment are very important for preventing scar formation. Overall, PDL treatment for PWS shows a high level of safety and low chances of causing long-term complications.

Efficacy and safety of 595-nm pulsed dye laser treating port wine stains in Vietnamese patients: analysis of 124 cases and optimal treatment regimens.

The purpose of this study is to determine the efficacy and safety of 595-nm pulsed dye laser (PDL) for port wine stains (PWS) treatment in Vietnamese patients. The study also analyzed the association between the response to treatment and the characteristics of patients and treatment regimens. Parallelly, the study contributed to further optimal treatment sessions for different subjects based on the data collected. One hundred twenty-five patients who underwent 595-nm PDL to treat PWS were included in the study, in which data from 124 patients was retrospectively analyzed. Data on demographic characteristics of patients, treatment regimens, and clinical improvement were collected. SPSS version 25 was used to analyze the relationship between associated factors and the response rate. The overall response rate of Vietnamese patients who had Fitzpatrick skin classification type III and IV was 73.4%. Age, gender, treatment sessions, and lesion positions were generally not associated with the response rate. The lesion grade was the sole element that affected the clinical improvement. The lesion grade 1 had the best response (100%) even after a short duration of treatment (six to ten treatments). Lesion grade 4 demanded over 16 treatments to reach > 60% of improvement. The lesion grades 1 and 2 could be blanched with regimen < 10 treatments while regimens exceeding 15 treatments should be carefully considered for lesions at grade 3 after evaluating associated conditions. Lesions at grade 4 demanded ≥ 16 treatments to reach acceptable outcomes. These results could help physicians establish a reasonable treatment strategy for patients.

Effect of Hemoporfin-mediated photodynamic therapy in the treatment of facial port-wine stains on intraocular pressure.

BACKGROUND: Photodynamic therapy (PDT) is a potential treatment for port-wine stains (PWS), but its effects on intraocular pressure (IOP) have not been reported. This study evaluated the efficacy of PDT for facial PWS and analyzed the changes in IOP before and after treatment. METHODS: Data from 32 patients with facial PWS who underwent single PDT treatment at our department were collected. The patients were divided into three groups based on the location of the PWS. Group A (15 cases) involved the eyelid of the eye being measured; Group B (10 cases) was located near the eyes but did not involve the measured eyelid; and Group C (7 cases) was situated on the face but not near the eyes. IOP measurements were taken before and after treatment, and the efficacy and changes in IOP were analyzed. RESULTS: The overall efficacy rates of single PDT were 84.37 %, demonstrating superior efficacy for the pink type, age < 6 years, and skin lesions < 10 cm2 (P < 0.05). The higher IOP was observed on the side with eyelid involvement of PWS (P < 0.001). The IOP of the affected side in Group A decreased by 2.13 ± 2.10 mmHg on average after treatment, which was statistically significant compared with the other two groups (P<0.05). CONCLUSIONS: Eyelid involvement in PWS increases the risk of elevated IOP. Hemoporfin-mediated PDT can reduce the IOP in patients with PWS involving the eyelid within a safe range. PDT for facial PWS is considered to be safe and effective.

Assessment of the efficacy of 595 nm pulsed dye laser in the management of facial flat angiomas. Results of a case series.

BACKGROUND: Studies on pulsed dye laser (PDL) have shown the best efficacy and safety data for treating vascular anomalies among the various lasers used and the 595-nm PDL has been used to treat cutaneous vascular anomalies for about 30 years. The purpose of this study was to assess the efficacy of 595 nm Pulsed Dye Laser in the management of facial flat angiomas present in the form of Port-Wine Stain. MATERIALS AND METHODS: Seven cases of PWS in Fitzpatrick skin type ranged from I to III and colour ranging from pink to purple, were treated with 595 nm pulse Dye Laser. Patients underwent to 6-8 laser sessions at 20-30 days intervals. Results obtained were judged by dermatologist, by comparing pre-treatment and post-treatment photographs, 6 months after the last session and a quartile scale of lesion clearance (4-point Investigator Global Assessment scale): 1 = no or low results (0%-25% of the lesion area improved), 2 = slight improvement (25%-50% of the lesion area cleared), 3 = moderate-good improvement (50%-75%), and 4 = excellent improvement (75%-100%) was used. Possible side effects such as blisters, hyper/hypopigmentation, and scarring were monitored. RESULTS: All patients observed global improvements. 71% of patients achieved excellent clearance and 29% patients achieved good-moderate clearance of their angioma. Patients were asked for a subjective evaluation of the results: 57% of patients were very satisfied, 29% were satisfied, and 14% patients were not very satisfied with the results. No patients were dissatisfied. No significant side effects were noted. CONCLUSION: This research confirms the efficacy of the 595 nm PDL for flat angioma management, without considerable side effects.

Parkes Weber syndrome: a rare cause of foot drop.

This case report describes a patient in her late 60s, previously diagnosed with Klippel-Trenaunay syndrome who presented with difficulty walking. A year prior to her presentation she had a fall which made her notice a painless foot drop on the right. Her right leg was profoundly hypertrophied compared with the left, and a port-wine stain was present on the lateral side, extending from the hip to the mid-shin. The patient's differential diagnosis based on clinical examination and investigations is discussed leading to a final diagnosis of sciatic neuropathy secondary to an arteriovenous malformation due to Parkes Weber syndrome.

Efficacy of hemoporfin-PDT on port-wine stains: A retrospective analysis of 2952 cases.

OBJECTIVE: To conduct a retrospective analysis of Hemoporfin photodynamic therapy (HMME-PDT) in the treatment of port-wine stains (PWS). METHOD: A retrospective analysis was conducted based on the clinical data from March 2017 to December 2022, so as to summarize the demographic characteristics, clinical efficacy and adverse reactions. The effectiveness of HMME-PDT was examined with respect to treatment times, age, gender, subtype, and location of PWS lesions. RESULT: The age of the 2952 cases ranged from 8 months to 56 years old (median, 2.8 years), with 1419 males (48.07 %), and 1533 females (51.93 %). There were 669 cases of pink type (22.66 %), 2184 cases of purplish red type (73.98 %), and 99 cases of nodular thickening type (3.35 %). The prevalence location was face (88.04 %), neck (14.94 %), limbs and trunk. 1602 cases (54.27 %) had never received treatment, 661 cases (22.39 %) had been treated by pulse dye laser (PDL), 229 cases (7.76 %) had previously been treated by PDT, 296 cases (10.03 %) had received both the modalities. The 2952 cases completed totally 7996 HMME-PDT times. Cure rate and effective rate increased continuously with the number of treatments. The pink type has the highest cure rate and effective rate, followed by the purplish red type and the last was the nodular thickening type. The therapeutic effects are considerably influenced by age, subtype, and treatment site (P < 0.05). However, there was no significant difference in the effectiveness of HMME-PDT between both genders. The local adverse reactions after the first treatment included edema (97.73 %), itching (82.62 %), purpura-like change (79.51 %), crusts (24.59 %), infection (4.07 %), scars (1.08 %), hyperpigmentation (0.61 %), and depigmentation (0.41 %). Nausea and vomiting occurred in 2 juveniles and 1 young adult (5, 6 and 22 years old respectively) immediately after treatment, and did not interfere with the administration of the treatment. Patients aged 21-30 were found to have a 3.4-fold higher likelihood of undergoing HMME-PDT under general anesthesia compared to those aged 15 or younger. There was no distinct systemic adverse reaction, such as allergic responses, cardiovascular effects, neurological symptoms, hematological abnormalities, respiratory symptoms, or musculoskeletal issues. CONCLUSION: HMME-PDT is preferred in treating PWS, with relatively high effective rate and cure rate, mild local reactions and no distinct systemic adverse reaction.