Sclerotherapy vs. surgical excision for lymphatic malformations of the head and neck: a systematic review and meta-analysis.

OBJECTIVES: Lymphatic malformations (LMs) are abnormal lymphatic vessels with cystic characteristics, categorized as macrocystic, microcystic, or a combination of both. They represent the second most common vascular malformations, and their management involves multidisciplinary approaches based on clinical assessments and imaging studies. LMs manifest as a challenge to medical professionals in the head and neck, posing functional and aesthetic concerns. Our systematic review aims to compare the efficacy of sclerotherapy and surgery for LMs, identifying optimal treatment modalities for each scenario. METHODS: We searched four electronic databases for related studies. Data were extracted from the included studies. We calculated the pooled rate ratios with 95% confidence intervals (CIs). The I2 test was used to detect heterogeneity. The inclusion of the studies required the following prerequisites: 1- Studies focusing on any lymphatic malformations in the head and neck, whether microcystic, macrocystic, or a mix of both; 2- Studies performed on more than ten patients; 3- All interventions used as surgery, sclerotherapy, or both. RESULTS: We included 58 studies in our systematic review, of which 45 were eligible for the meta-analysis. For macrocystic LMs, sodium tetradecyl sulfate (STS) mixed with ethanol and excision achieved the highest complete response rates at (92.9%) and (92.5%), respectively. Surgical excision showed the lowest poor response rate. Polidocanol microfoam had the highest poor response rate (11.1%). In microcystic LMs, combining sclerotherapy with excision showed the highest complete response rate (70.3%) and the lowest poor response rate (1.3%). Picibanil had the lowest complete response rate (9.1%) and the highest rate of poor response (61.4%). In mixed LMs, surgical excision had the highest complete response rate (70.3%). CONCLUSION: Both surgical excision and STS combined with ethanol are highly effective for treating macrocystic LMs, achieving similar complete response rates. The combination of sclerotherapy and surgical excision demonstrated the best outcomes in microcystic LMs. Surgical excision demonstrates superior efficacy over sclerotherapy for mixed LMs. These findings suggest that excision is generally more effective in achieving complete and excellent responses across all LM subtypes. Further high-quality studies are necessary to standardize and optimize treatment protocols.

Complications of pediatric macrocystic lymphatic malformations of the head and neck: a survival analysis of treated and untreated patients.

OBJECTIVE: To compare events of recurrent swelling between treated and untreated patients with macrocystic lymphatic malformations of the head and neck not involving the airway. The frequency and timing of emergency department (ED) visits related to the event were analysed to provide data on efficacy and ideal timing of treatment. METHODS: A 5-year retrospective review of a hospital database was conducted reviewing 35 patients (15 female, 20 male; mean age 3.9 years) with macrocystic lymphatic malformations of the head and neck not involving the airway. Patients treated with oral medications were excluded. A survival analysis was performed comparing the incidence of recurrent swelling of the malformation. A Cox regression analysis was conducted using age, gender, diameter of lymphatic malformation at presentation, and echogenicity on US as covariates. Fisher's test and mean comparisons were performed to correlate the populations baselines and the number and frequency of ED visits between the 2 groups. RESULTS: Thirteen patients underwent sclerotherapy soon after initial presentation and 22 elected for observation. The two baseline populations differed at presentation with the treatment group being younger (1.4 ± 2.4 vs. 5.4 ± 6.3 years, p = 0.03) and with larger lesions (5.7 ± 2.7 vs. 4.0 ± 1.7 cm p = 0.03). Mean follow-up time was 2.7 years. Survival analysis showed 1 or multiple recurrences affected 16 patients in the untreated group and 3 patients in the treated group. (p = 0.04). Age, gender, diameter of the lesion at presentation and increased echogenicity on US were not predictive factors of recurrence. Although the probability of visiting the ED at least once did not differ between the two groups (p = 0.42), patients from the non-treatment group were more likely to visit the ED more than once (p = 0.03). CONCLUSIONS: Sclerotherapy treatment may reduce the chance of recurrent swelling or an event after initial presentation to the ED.

A multi-step approach to overcome challenges in the management of head and neck lymphatic malformations, and response to treatment.

BACKGROUND: Lymphatic malformations are vascular developmental anomalies varying from local superficial masses to diffuse infiltrating lesions, resulting in disfigurement. Patients' outcomes range from spontaneous regression to severe sequelae notwithstanding appropriate treatment. The current classification guides, in part, clinicians through the decision-making process, prognosis prediction and choice of therapeutic strategies. Even though the understanding of molecular basis of the disease has been recently improved, a standardized management algorithm has not been reached yet. RESULTS: Here, we report our experience on five children with different lymphatic anomalies of the head and neck region treated by applying a multidisciplinary approach reaching a consensus among specialists on problem-solving and setting priorities. CONCLUSIONS: Although restitutio ad integrum was rarely achieved and the burden of care is challenging for patients, caregivers and healthcare providers, this study demonstrates how the referral to expert centres can significantly improve outcomes by alleviating parental stress and ameliorating patients' quality of life. A flow-chart is proposed to guide the multidisciplinary care of children with LMs and to encourage multidisciplinary collaborative initiatives to implement dedicated patients' pathways.

Laparoscopic-assisted sclerotherapy in pediatric retroperitoneal lymphatic malformations.

Background: Retroperitoneal lymphatic malformations (LMs) are rare. Currently, the treatment of retroperitoneal LMs remains challenging. This study aimed to examine the safety and efficacy of laparoscopic-assisted sclerotherapy for retroperitoneal LMs in pediatric patients. Methods: We retrospectively reviewed patients treated with laparoscopic-assisted sclerotherapy for retroperitoneal LMs in a single tertiary medical center between July 2020 and February 2023. Doxycycline was prepared into a solution with a concentration of 10 mg/ml for use in sclerotherapy. Demographic data, clinical features, details of management, and outcomes were collected and analyzed. Results: A total of six patients, comprising three males and three females, were identified. The LMs were categorized into four macrocystic and two mixed-cystic types. The mean age and weight were 52.2 months (range, 11-108 months) and 20 kg (range, 12.5-27.5 kg), respectively. Three patients presented with abdominal pain or distension, while the other three patients were asymptomatic. All six patients underwent a total of eight sclerotherapy sessions. Two patients experienced intra-cystic hemorrhage and required a second sclerotherapy session. Only one patient presented with vomiting after sclerotherapy, which resolved spontaneously. Five patients met the complete response criteria, and one patient met the effective criteria. The mean reduction in lesion size was 92.3% (range, 69.9%-99.6%). No further complications or recurrence were recorded during follow-up. Conclusion: Laparoscopic-assisted sclerotherapy is a safe and effective approach for treating retroperitoneal LMs. This technique is applicable for both macrocystic and mixed-cystic retroperitoneal LMs.

A 14-year single-center experience evaluating sclerotherapy efficacy in lymphatic malformations.

OBJECTIVE: The aim of this study is to share our experience in treating patients with lymphatic malformations (LMs) over a span of 14 years, evaluating the efficacy and safety of sclerotherapy, particularly with the use of ethanol as sclerosant of choice. METHODS: A retrospective review of pediatric patients diagnosed and later treated for LMs between 2008 and 2022 was conducted. We collected patient demographics, LM characteristics, treatment strategies, and outcomes, including response to treatment and complications. RESULTS: The cohort included 36 patients (24 male patients), first presenting clinically at a median age of 5 months (range: 0-12 years). LMs were macrocystic (17), microcystic (3), and mixed types (16). In most patients (22), the malformation involved the cervicofacial area. Twenty-five patients underwent 54 procedures, averaging 2 procedures per patient (range: 1-13). Sclerotherapy resulted in 90% of patients exhibiting some response of the LM (P = .005). Ethanol was used in most procedures (31) and proved most efficacious, facilitating partial or complete response of the malformations in all cases compared with 72% with other sclerosants (P = .06). Sclerotherapy exhibited low complication rates among all sclerosants used (7%, P = .74). CONCLUSIONS: Sclerotherapy is a safe and effective intervention for pediatric LMs. Ethanol demonstrated comparable efficacy and safety to other sclerosants, highlighting its potential as a preferred treatment option. This study supports the tailored use of sclerotherapy, guided by a thorough understanding of the risks and benefits, to provide optimized care for patients with LMs.

Congenital Vascular Malformations in Children: From Historical Perspective to a Multidisciplinary Approach in the Modern Era-A Comprehensive Review.

Congenital vascular malformations (CVMs) are the result of an aberrant development during embryogenesis. Although these lesions are present at birth, they are not always visible yet. Once symptomatic, patients suffer from pain, bleeding, ulcers, infections or lymphatic leakage, depending on the subtype of vessels involved. Treatment includes conservative management, surgery, sclerotherapy, embolization and pharmacological therapy. The clinical presentation varies widely and treatment can be challenging due to the rarity of the disease and potential difficulties of treatment. This review gives an overview of the historical developments in diagnosis and classification and exposes the key elements of innovations in the past decades on the identification of genetic mutations and personalized treatment. These advances in the field and a multidisciplinary approach are highly valuable in the optimization of clinical care aimed at both curing or stabilizing the CVM and pursuing physical and psychosocial wellbeing.

Successful Management of Retropharyngeal Lymphangioma with Stridor Using Sirolimus: A Case Report.

Lymphatic malformations (LMs) are one of the congenital malformations of the lymphatic system in the body. The patient usually presents with head and neck swelling, airway compression, and/or airway obstruction. The diagnosis of retropharyngeal LMs can be challenging due to their rare occurrence. We report a case of a five-month-old boy diagnosed with retropharyngeal LMs. He presented with a three-day history of fever, cough, and stridor and was initially treated for acute bronchiolitis. A lateral neck radiograph revealed prevertebral widening, suggesting retropharyngeal collection. The patient's condition worsened, requiring intubation in the operating room and proceeding with aspirations and drainage. However, the symptoms recurred after a few days, necessitating re-intubation, repeated aspirations and drainage procedures. The patient was intubated, and the neck's magnetic resonance imaging (MRI) confirmed retropharyngeal LMs. An elective tracheostomy was performed and was treated with sirolimus. The patient had a successful tracheostomy decannulation and showed no recurrence during follow-up.

Interrelation of cancers of unknown primary, chylous ascites, and cavernous mesenteric lymphangioma in a 57-year-old female patient: a case report.

Cancers of unknown primary (CUPs) pose diagnostic and therapeutic challenges because of their aggressive nature and elusive identification through conventional diagnostic means. This case report presents a unique finding in a 57-year-old female patient who, alongside her CUP, developed a cavernous mesenteric lymphangioma-a rare lymphatic malformation that is more commonly observed in pediatric populations. The interrelation between CUPs, chylous ascites, and lymphangiomas is explored, shedding light on this uncommon occurrence. Our patient's journey began with a CUP diagnosis, marked by metastatic adenocarcinoma. Subsequent symptoms led to the discovery of a mesenteric lymphangioma. The case unfolds the patient's diagnostic challenges, surgical interventions, and postoperative course. By highlighting the distinctive features of our case, we aim to contribute to the limited understanding of the interplay between lymphatic malformations and metastatic malignancies.

Differential Diagnosis of Generalized Cystic Lymphangiomatosis: A Literature Review.

BACKGROUND: Generalized cystic lymphangiomatosis (GCL) is a rare disease characterized by the widespread proliferation of lymphatic vessels, often seen in the pediatric patient group. Imaging techniques are instrumental in revealing the extent and morphological features of the disease. OBJECTIVE: The objective of this study is to interpret the radiological findings of GCL and address the differential diagnosis between GCL and other lymphatic malformations in light of the relevant literature data. METHODS: The sample of this retrospective study consisted of six pediatric patients, four males and two females, diagnosed with GCL based on clinical, radiological, and histopathological findings between 2015 and 2022. The age of the patients at the time of diagnosis and their symptoms at admission were obtained from the hospital database. Radiological imaging findings were evaluated in detail based on the involved systems (thorax, abdomen, and musculoskeletal). RESULTS: The median age of the sample, 4/6 were male, was 9 years at admission (min. 3, max. 12). The most common symptom at admission was dyspnea, often accompanied by pleural effusion. Bone involvement was the most common extrathoracic finding. Abdominal involvement was primarily asymptomatic, and the spleen was the most frequently involved organ in the abdomen. CONCLUSION: The diagnosis of GCL is challenging because of its rarity and overlapping diseases. Whole-body magnetic resonance imaging is a valuable tool as it reveals the typical radiological features of GCL and how far it has spread throughout the body.

Efficacy of Bleomycin-Lauromacrogol Foam in Pediatric Macrocystic Lymphatic Malformations With and Without Intracapsular Hemorrhage.

BACKGROUND: Sclerotherapy is purportedly less effective in patients with hemorrhagic than with non-hemorrhagic lymphatic malformations (LMs). We aimed to compare the efficacy of bleomycin-lauromacrogol foam (BLF) sclerotherapy in the treatment of macrocystic LMs with and without intralesional hemorrhage. METHODS: Fifty-five children with macrocystic LMs admitted to the Pediatric Surgery Department were retrospectively included. The patients were allocated into a hemorrhage group (23 cases) or a non-hemorrhage group (32 cases) based on the occurrence of an intracapsular hemorrhage. The diagnosis was confirmed by physical examination, color ultrasound, magnetic resonance imaging, and puncture findings. BLF was injected into the capsule after draining the cystic fluid under color ultrasound guidance. Patients whose lesions were unchanged or showed minor change after 1 month were treated again using the same method. Changes in lesion size and the number of treatments were recorded. Effectiveness was classified as excellent (volume reduction ≥90%), good (50%≤volume reduction<90%), or poor (volume reduction <50%). RESULTS: In the hemorrhage group, 17, 6, and 0 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 100%. In the non-hemorrhage group, 23, 7, and 2 patients' outcomes were classified as excellent, good, and poor, respectively. The overall efficacy rate was 93.8%. There was no significant difference in efficacy rate between groups (P = 0.767). CONCLUSIONS: BLF is an effective and safe treatment for macrocystic LMs with bleeding. The results were similar in patients with and without bleeding. LEVEL OF EVIDENCE: Treatment, Level III.

Imaging manifestations of head and neck lymphatic malformations: A single-center experience of 170 surgical cases.

OBJECTIVES: To discuss the imaging manifestations and the utility of preoperative ultrasonography (US), contrast-enhanced computed tomography (CE-CT) and contrast enhanced magnetic resonance imaging (CE-MRI) in diagnosing the pediatric head and neck lymphatic malformations (HNLMs). METHODS: We performed a retrospective review of 170 children who were referred to our hospital in the past 9 years for the treatment of HNLMs. RESULTS: The diagnostic rates of US, CE-CT and CE-MRI were 93.0% (146/157), 94.7% (143/151) and 100% (45/45), respectively. As in multilocular cases, intracystic septa detection rate was 91.5% (130/142), 50.4% (68/135) and 88.1% (37/42), and which had a statistical difference (χ2 = 25.8131, p < 0.05). US showed capsule contents anechoic in 51.0% (80/157) cases, hypoechoic or mixed echoic in 49.0% (77/157) cases, and flocculent or dotted echo floating in 36.9% (58/157) cases. CT showed low density of the capsule contents without enhancement in 69.5% (105/151) cases and mixed density with enhancement in 30.4% (46/151) cases. Liquid-liquid levers were seen in 8.6% (13/151) cases. MRI showed T1WI high signal and T2WI low signal of the capsule contents without enhancement in 28.9% (13/45) cases and mixed density in 71.1% (32/45) cases. Liquid-liquid levers were seen in 46.7% (21/45) cases. There were statistically significant differences between pure HNLMs and intracystic hemorrhage in capsule content (echo, density, signal), enhancement, and liquid-liquid lever (all p < 0.05). Among US, CE-CT and CE-MRI, intracystic hemorrhage diagnostic accuracy had a statistical difference (χ2 = 25.4152, p < 0.05). CONCLUSIONS: For clinical diagnosis and evaluation of HNLMs, we suggest that US combined with CE-CT for acute cases, and for stable cases, US combined with CE-MRI.

The role of key biomarkers in lymphatic malformation: An updated review.

The lymphatic system, crucial for tissue fluid balance and immune surveillance, can be severely impacted by disorders that hinder its activities. Lymphatic malformations (LMs) are caused by fluid accumulation in tissues owing to defects in lymphatic channel formation, the obstruction of lymphatic vessels or injury to lymphatic tissues. Somatic mutations, varying in symptoms based on lesions' location and size, provide insights into their molecular pathogenesis by identifying LMs' genetic causes. In this review, we collected the most recent findings about the role of genetic and inflammatory biomarkers in LMs that control the formation of these malformations. A thorough evaluation of the literature from 2000 to the present was conducted using the PubMed and Google Scholar databases. Although it is obvious that the vascular endothelial growth factor receptor 3 mutation accounts for a significant proportion of LM patients, several mutations in other genes thought to be linked to LM have also been discovered. Also, inflammatory mediators like interleukin-6, interleukin-8, tumor necrosis factor-alpha and mammalian target of rapamycin are the most commonly associated biomarkers with LM. Understanding the mutations and genes expression responsible for the abnormalities in lymphatic endothelial cells could lead to novel therapeutic strategies based on molecular pathways.

Sirolimus for Pediatric Cervicofacial Lymphatic Malformation: A Systematic Review and Meta-Analysis.

OBJECTIVE: This study is a systematic review and meta-analysis of the efficacy and safety of sirolimus in the management of pediatric cervicofacial lymphatic malformations (LMs). DATA SOURCES: EMBASE, Medline, Scopus, and Cochrane databases were searched, along with the reference list of all included articles. REVIEW METHODS: The study protocol was registered with PROSPERO and a systematic literature search strategy was designed and conducted with the aid of a medical librarian. All studies including case reports were included, with pooled analysis of raw data. A meta-analysis was conducted of magnetic resonance imaging (MRI), clinical, and airway outcomes. RESULTS: Thirteen case series and five individual case reports were included. Meta-analysis showed 78% (95% CI 57%-94%) of 62 patients had a reduction in LM volume, on MRI criteria, by 20% or more, and 32% (95% CI 11%-57%) had a reduction of 50% or more. Further meta-analysis showed 97% (95% CI 88%-100%) of 78 patients reported some clinical improvement on sirolimus. Sirolimus may be of particular value in management of airway LMs; out of 27 tracheostomy-dependent patients, meta-analysis showed 33% (95% CI 1%-78%) were decannulated after starting sirolimus. Individual patient meta-analysis on 24 individuals showed a statistically significant better response to sirolimus when initiated under the age of 2 years. CONCLUSION: This review and meta-analysis support the efficacy of sirolimus in pediatric LMs of the head, neck, and airway. A large multi-center trial is needed to further explore its role and limitations. Laryngoscope, 134:2038-2047, 2024.

The value of MRI in the diagnosis of pediatric head and neck lymphatic malformations: A study of 46 surgical cases.

Objective To discuss the value of MRI in diagnosing and evaluating the pediatric head and neck lymphatic malformations (HNLMs). Methods We performed a retrospective review of 46 children who were referred to our hospital in the last decade for the treatment of HNLMs. Results About 34 cases confirmed with intralesional hemorrhage while the capsule contents were dark red or light bloody liquid. The remaining 12 pure HNLMs were filled with yellow clear or watery liquid. The multilocular HNLMs accounted for 95.7 % (44/46). The accuracy of contrast enhanced MRI (CE-MRI) diagnosis of HNLMs was 100 %. On MRI, the HNLMs appeared as irregular shape [95.7 % (44/46)], clear boundary [91.3 % (42/46)], infiltrative growth [91.3 % (42/46)] cystic masses. The cystic wall and septa were hyperintense on T1WI and hypointense on T2WI (100 %), and displayed enhancement. The capsule contents had hypointense on T1WI and hyperintense on T2WI in 18 cases (pure HNLMs,12; intracystic hemorrhage,6), while that of mixed signal in 28 cases (pure HNLMs,0; intracystic hemorrhage,28). Capsule contents were enhanced in 22 cases (pure HNLMs,1; intracystic hemorrhage,21), while the remaining 24 without enhancement (pure HNLMs,11; intracystic hemorrhage,13). Liquid-liquid levers were found in 21 cases (pure HNLMs,0; intracystic hemorrhage,21). There were statistical differences in capsule contents signal, enhancement, and liquid-liquid levels between the two groups (P < 0.05). Conclusions On MRI, HNLMs typically show a thin-walled, well-circumscribed, irregularly shaped, infiltrative, unenhanced, multilocular cystic mass with hypointense on T1WI and hyperintense on T2WI. The capsule wall and septa are hyperintense on T1WI, hypointense on T2WI, and display enhancement. Changes in the signal of capsule contents or appearance of liquid-liquid levels indicate intracystic hemorrhage.

A case series of fetal lymphatic malformations and a review of the literature.

Lymphatic malformations are rare benign developmental anomalies of the lymphatic system that can be diagnosed by prenatal ultrasound. Depending on their anatomical site and size, the lesions can cause a variety of aesthetic and functional deficits. Several treatment options are available, the most suitable is still under debate. The experience gained at our Centre and the review of the literature can be useful to improve prenatal counseling, that is challenging due to the heterogeneity of clinical presentation and treatment.

Generalized Lymphatic Anomaly as a Differential Diagnosis of Lytic Lesions.

Generalized lymphatic anomaly (GLA) is an infrequent multiorgan disease characterized by the presence of abnormal proliferation of lymphatic vessels. The diagnosis requires histological confirmation, and the treatment is controversial. We are presenting a case of a 28-year-old male patient who was diagnosed with an extragonadal mediastinal nonseminomatous germ cell tumor. He underwent chemotherapy, and during this treatment, radiologic findings evidenced lytic lesions. Multiple biopsies were performed, which revealed the presence of abnormal lymphatic vessels, characteristic of GLA. There are different etiologies of osteolytic lesions, and on some occasions, they mimic a tumoral entity. The clinical suspicion of GLA is the first step in approaching the diagnosis, particularly in young adult patients.

Rapid response with good toleration of sirolimus for life-threatening neonatal lymphatic malformations.

Introduction: Lymphatic malformations (LMs) are rare vascular anomalies predominantly affecting infants, which can be debilitating or life-threatening when complicated with intralesional bleeding or infection. Effective and safe management strategies are essential in such cases. Case presentation: We report a case series involving four Chinese neonates with life-threatening LMs, initially treated with oral sirolimus. All patients achieved rapid relief and sustained remission, using a lower sirolimus dosage than previously recommended. Furthermore, adverse events were rarely recorded during follow-up. Conclusion: Sirolimus can be considered a promising choice for neonates with intricate and life-threatening LMs. Initiation with a reduced sirolimus dose is advisable.

Health-related quality of life in children with congenital vascular malformations.

A cross-sectional study was performed to evaluate health-related quality of life (HRQOL) in children with congenital vascular malformations (CVM) and to investigate factors associated with an impaired HRQOL. Children (2-17 years) with CVMs who visited the HECOVAN expertise center between 2016-2018 were included. The PedsQL 4.0 Generic Core Scales were used and a score ≥ 1.0 SD below the normative mean was defined as an impaired HRQOL. Factors associated with impairment were investigated using univariate and multivariate logistic regression analysis. The median overall HRQOL was 84.8/100 (n = 207; 41% boys, 59% girls; self-reported IQR 73.9-92.4 and parent-reported IQR 71.4-92.4). Patients aged 13-17 years reported significantly worse physical functioning than those aged 8-12 years (median 84.4, IQR 71.1-93.8 versus median 90.6, IQR 81.3-96.9; p = 0.02). Parents reported a significantly lower overall HRQOL than their children (median 80.4, IQR 70.7-90.8 versus median 85.9, IQR 76.1-92.4; p = 0.001). HRQOL was impaired in 25% of patients. Impairment occurred significantly more often in lower extremity CVMs (38%, p = 0.01) and multifocal CVMs (47%, p = 0.01) compared to CVMs in the head/neck region (13%). Other associated factors included invasive management (31% versus 14%; p = 0.01), age at first treatment ≤ 5 years (48% versus 25%; p = 0.02) and ongoing treatment (38% versus 18%; p = 0.004). After correction for other factors, significance remained for lower extremity CVMs and ongoing invasive treatment. CONCLUSIONS: Overall median HRQOL was reasonable and not significantly different from the norm sample. Parental ratings were significantly lower than their children's ratings. A quarter of the patients had an impaired HRQOL, which seemed to worsen with age. Independently associated factors included a lower extremity CVM and invasive management. WHAT IS KNOWN: • Congenital vascular malformations could affect health-related quality of life (HRQOL). • Studies on pediatric patients are limited and either very small or in combination with adult patient series. WHAT IS NEW: • This study raises awareness of an impaired HRQOL in 25% of pediatric patients with congenital vascular malformations. • Associated factors included a lower extremity CVM and invasive management.

The efficacy of bleomycin sclerotherapy in the treatment of lymphatic malformations: a review and meta-analysis.

OBJECTIVE: At present, bleomycin has been widely used in the treatment of Lymphatic Malformations (LMs). This study aims to perform a meta-analysis to investigate the effectiveness and influencing factors of bleomycin in the treatment of LMs. METHODS: We conducted a systematic review and meta-analysis to clarify the relationship between bleomycin and LMs. PubMed, ISI Web of Science and MEDLINE were searched. RESULTS: A total of 21 studies (including 428 cases) about bleomycin sclerotherapy for LMs were included in the current meta-analyses. We calculated pooled effective rate and 95% Confidence Interval (95% CI) using random effects model to evaluate the relations between bleomycin and LMs. The results suggested that the effective rate of bleomycin was the combined effective rate was 84.0% (95% CI 0.81‒0.87) and ranged from 39% (95% CI 0.22‒0.56) to 94% (95% CI 0.87-1.02). The heterogeneity among the studies was substantial (I2=61.7%, p= 0.000). In subgroup analyses, it was observed that among retrospective study and prospective study, the estimated effective rate was 80.0% (95% CI 0.76‒0.84) and 91.0% (95% CI 0.85‒0.97), respectively. In terms of the dosage, the combined effective rates of weight-based group and fixed-dose group were 86% (95% CI 0.83‒0.90) and 74.0% (95% CI 0.66‒0.82), respectively. There was no significant publication bias in Egger's test (p=0.059, 95% CI -3.81 to 0.082), but Begg's test did (p=0.023), and the funnel plot is asymmetric. CONCLUSION: Our study suggested that bleomycin was safe and effective in the treatment of LMs and was primarily dose dependent.

VEGF-C overexpression in kidney progenitor cells is a model of renal lymphangiectasia.

Background: Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease.As injury related lymphangiogenesis is driven by signaling from the receptor VEGFR-3 in response to the cognate growth factor VEGF-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remains poorly defined. Methods: We generated a new mouse model expressing Vegf-C under regulation of the nephron progenitor Six2Cre driver strain (Six2Vegf-C). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and micro computed tomography 3-dimensional imaging. Results: Six2Vegf-C mice had reduced body weight and kidney function compared to littermate controls. Six2Vegf-C kidneys demonstrated large peripelvic fluid filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. 3D imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+/PDPN+/VEGFR3+ lymphatic capillaries extending alongside EMCN+ peritubular capillaries. There was no change in EMCN+ peritubular capillary density. Conclusions: Kidney lymphangiogenesis was robustly induced in the Six2Vegf-C mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR-3. The model resulted in a severe cystic kidney phenotype that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGF-C signaling during kidney development and provides new insight into a mimicker of human cystic kidney disease.