Intralesional bleomycin injection treatment of intra-abdominal lymphangiomas presenting with acute abdomen in children.

BACKGROUND: We evaluated the results of urgent intralesional bleomycin injection (IBI) treatment of intra-abdominal lymphan-giomas (IAL) presenting with acute abdomen in children. METHODS: The records of patients who underwent urgent IBI due to acutely presenting IAL between January 2013 and January 2020 were reviewed retrospectively in terms of age, presenting symptoms, cyst type, number of injections, pre- and post-treatment cyst volume, clinical response, complications, and follow-up. RESULTS: Six patients with a mean age of 4.3 years (2-13 years) were treated. Presenting symptoms were acute abdominal pain (n=4), abdominal distention (n=1), hypoproteinemia and chylous ascites (n=1). Lesions were of macrocystic type in four and macro and micro cystic in two patients. The median number of injections performed was 2 (1-11). Mean cyst volume reduced dramatically from 567 cm3 (range 117-1656) to 3.4 cm3 (range 0-13.8) after treatment (p=0.028). Treatment response was excellent in four patients with complete resolution of the cysts, while good in the remaining two. No early or late complications or recurrence was observed in a mean follow-up period of 40 months (16-56 months). CONCLUSION: IBI is a safe, fast, and easily applicable method with satisfactory results in the treatment of acutely presenting IAL. It may be recommended in primary as well as recurrent lesions.

Genomic landscape of lymphatic malformations: a case series and response to the PI3Kα inhibitor alpelisib in an N-of-1 clinical trial.

Background: Lymphatic malformations (LMs) often pose treatment challenges due to a large size or a critical location that could lead to disfigurement, and there are no standardized treatment approaches for either refractory or unresectable cases. Methods: We examined the genomic landscape of a patient cohort of LMs (n = 30 cases) that underwent comprehensive genomic profiling using a large-panel next-generation sequencing assay. Immunohistochemical analyses were completed in parallel. Results: These LMs had low mutational burden with hotspot PIK3CA mutations (n = 20) and NRAS (n = 5) mutations being most frequent, and mutually exclusive. All LM cases with Kaposi sarcoma-like (kaposiform) histology had NRAS mutations. One index patient presented with subacute abdominal pain and was diagnosed with a large retroperitoneal LM harboring a somatic PIK3CA gain-of-function mutation (H1047R). The patient achieved a rapid and durable radiologic complete response, as defined in RECIST1.1, to the PI3Kα inhibitor alpelisib within the context of a personalized N-of-1 clinical trial (NCT03941782). In translational correlative studies, canonical PI3Kα pathway activation was confirmed by immunohistochemistry and human LM-derived lymphatic endothelial cells carrying an allele with an activating mutation at the same locus were sensitive to alpelisib treatment in vitro, which was demonstrated by a concentration-dependent drop in measurable impedance, an assessment of cell status. Conclusions: Our findings establish that LM patients with conventional or kaposiform histology have distinct, yet targetable, driver mutations. Funding: R.P. and W.A. are supported by awards from the Levy-Longenbaugh Fund. S.G. is supported by awards from the Hugs for Brady Foundation. This work has been funded in part by the NCI Cancer Center Support Grants (CCSG; P30) to the University of Arizona Cancer Center (CA023074), the University of New Mexico Comprehensive Cancer Center (CA118100), and the Rutgers Cancer Institute of New Jersey (CA072720). B.K.M. was supported by National Science Foundation via Graduate Research Fellowship DGE-1143953. Clinical trial number: NCT03941782.

Complex lymphatic malformations in pediatrics: a review of treatment options.

INTRODUCTION: Lymphatic malformations (LMs) are low-flow lesions resulting from abnormalities in the development of lymphatics. The management of these lesions is complex and involve the collaboration of many specialties. The purpose of this review is to summarize current knowledge regarding the different therapeutic options used in complex lymphatic malformations, analyzing their indications, efficacy and complications. EVIDENCE ACQUISITION: A search was made using the algorithm: "(lymphatic abnormality OR lymphatic malformation OR lymphangioma OR cystic hygroma) AND (extensive OR giant OR complex) AND (therapeutics OR treatment) AND (child OR children)". Of the 120 articles found, 53 were included. EVIDENCE SYNTHESIS: Historically, surgery was the treatment of choice for this type of lesions. However, excision was often incomplete, associated with high rates of recurrence and severe complications. The use of sclerotherapy emerged as a minimal invasive option appropriate in selected cases as a single or adjuvant therapy. Inhibitors of the mammalian target of rapamycin, such as sirolimus, now play a central role in the treatment of complex malformations resistant to sclerotherapy, recurrent after surgery or more extensive malformations that affect vital structures. Other therapeutic options as sildenafil and laser ablation are also recognized as effective in selected cases. CONCLUSIONS: Looking through the literature over the last decade authors realize that surgery had gradually been replaced by less invasive options such as sirolimus with or without adjuvant sclerotherapy. In conclusion, each treatment option seems to have its own indications and characteristics, which must be considered in therapeutic decision and individualized for each patient.

Aminolevulinate photodynamic therapy (ALA-PDT) combined with fire needle for vulva lymphangioma circumscriptum.

Lymphangioma is a rare benign lymphatic system proliferation, especially in the vulva. The general treatment principle is determined by clinical manifestations, lesion size, anatomic location, and complications. Treatment options include surgical excision, carbon dioxide laser, cryotherapy, electrocoagulation, and sclerosing agent injection. In the absence of evidence to guide the choice of significant treatment modalities, treatment options are often based on the experience of the treatment team and the patient's preferences. This study presents a case of primary vulva lymphangioma circumscriptum treated with fire needle therapy, photodynamic therapy, and cryotherapy. Furthermore, the combination of fire needle and photodynamic therapy demonstrated exceptional comprehensive effects in pain, wound healing and cosmetic.

Disseminated lymphangiomas as a cutaneous manifestation of Noonan syndrome.

Lymphangioma is a known, but rare manifestation of Noonan syndrome. We present the case of disseminated and circumscribed cutaneous lymphangiomas in the context of Noonan syndrome. Oral rapamycin is a promising treatment in these extensive and morbidity-causing cases.

Computed Tomography Image Characteristics before and after Interventional Treatment of Children's Lymphangioma under Artificial Intelligence Algorithm.

The artificial intelligence algorithm was used to analyze the characteristics of computed tomography (CT) images before and after interventional treatment of children's lymphangioma. Retrospective analysis was performed, and 30 children with lymphangioma from the hospital were recruited as the study subjects. The ultrasound-guided bleomycin interventional therapy was adopted and applied to CT scanning through convolutional neural network (CNN). The CT imaging-related indicators before and after interventional therapy were detected, and feature analysis was performed. In addition, the CNN algorithm was adopted to segment the image of the tumor was clearer and more accurate. At the same time, the Dice similarity coefficient (DSC) of the CNN algorithm was 0.9, which had a higher degree of agreement. In terms of clinical symptoms, the cured children's lesions disappeared, the skin surface returned to normal color, and the treatment was smooth. In the two cases with effective treatment, the cystic mass at the lesion site was significantly smaller, and the nodules disappeared. CT images before interventional therapy showed that lymphangiomas in children were more common in the neck. The cystic masses at all lesion sites varied in diameter and size, and most of them were similar to round and irregular, with uniform density distribution. The boundary was clear, the cyst was solid, and there were different degrees of compression and spread to the surrounding structure. Most of them were polycystic, and a few of them were single cystic. After interventional treatment, CT images showed that 27 cases of cured children's lymphangioma completely disappeared. Lymphangioma was significantly reduced in two children with effective treatment. Edema around the tumor also decreased significantly. Patients who did not respond to the treatment received interventional treatment again, and the tumors disappeared completely on CT imaging. No recurrence or new occurrence was found in three-month follow-up. The total effective rate of interventional therapy for lymphangioma in children was 96.67%. The CNN algorithm can effectively compare the CT image features before and after interventional treatment for children's lymphangioma. It was suggested that the artificial intelligence algorithm-aided CT imaging examination was helpful to guide physicians in the accurate treatment of children's lymphangioma.

Evaluación del tratamiento de linfangiomas con bleomicina en población pediátrica de 0 a 18 años / Evaluation of the treatment of lymphangiomas with bleomycin in a pediatric population aged 0 to 18 years

INTRODUCCIÓN. Los linfangiomas son una malformación infrecuente a escala mundial y constituye una preocupación para los padres del infante; está asociado a problemas estéticos y a posibles efectos deletéreos debido a la obstrucción o compresión de órganos vitales. Se ha descrito a la escleroterapia como la mejor opción de tratamiento. OBJETIVO. Determinar la eficiencia del tratamiento con bleomicina en linfangiomas en la población pediátrica de 0 a 18 años. MATERIALES Y MÉTODOS. Estudio transversal analítico retrospectivo. Población y muestra conocida de 20 datos de Historias Clínicas electrónicas de pacientes diagnosticados con linfangiomas y tratados con bleomicina en el Hospital de Especialidades Carlos Andrade Marín, desde enero 2015 a enero 2018. Criterios de inclusión: pacientes de 0 a 18 años de edad con diagnóstico de linfangioma mediante ecografía y angiotomografía computarizada. Criterios de exclusión: pacientes mayores de 18 años de edad o sospecha diagnóstica de linfangioma sin estudios de imagen, y/o que no acudieron a la cita de control, pacientes diagnosticados de linfangioma que no recibieron bleomicina para su tratamiento, niños con otras malformaciones vasculares. El análisis de datos se realizó en el programa estadístico International Business Machines Statistical Package for the Social Sciences. RESULTADOS. La mediana de edad en mujeres fue de 6,25 años y 3,8 años en hombres. 10 pacientes fueron hombres. El promedio de seguimiento fue de 26,86 +/- 16,78 meses. El tamaño promedio de los linfangiomas fue de 5,77 +/- 3,73 cm. La localización más frecuente fue cervical con un 52,38%. La mayoría fueron macronodulares con un 85,71%. La respuesta fue buena o excelente en el 81,00% de los casos con la primera infiltración y subió al 95,00% con la segunda y tercera, según requerimiento. CONCLUSIÓN. El tratamiento de los linfangiomas con bleomicina fue muy efectivo en la población estudiada.

INTRODUCTION. Lymphatic malformation is a rare malformation worldwide and is a concern for the parents of the infant; it is associated with aesthetic problems and possible deleterious effects due to obstruction or compression of vital organs. Sclerotherapy has been described as the best treatment option. OBJECTIVE. To determine the efficiency of bleomycin treatment in lymphangiomas in the pediatric population aged 0 to 18 years. MATERIALS AND METHODS. Retrospective analytical cross-sectional study. Population and known sample of 20 data from Electronic Medical Records of patients diagnosed with lymphangiomas and treated with bleomycin at the Carlos Andrade Marín Specialties Hospital, from January 2015 to January 2018. Inclusion criteria: patients aged 0 to 18 years with diagnosis of lymphangioma by ultrasound and computed angiotomography. Exclusion criteria: patients older than 18 years of age or diagnostic suspicion of lymphangioma without imaging studies, and/or who did not attend the control appointment, patients diagnosed with lymphangioma who did not receive bleomycin for treatment, children with other vascular malformations. Data analysis was performed in the statistical program International Business Machines Statistical Package for the Social Sciences. RESULTS. The median age in women was 6,25 years and 3,8 years in men. Ten patients were men. The average follow-up was 26,86 +/- 16,78 months. The average size of the lymphatic malformations was 5,77 +/- 3,73 cm. The most frequent location was cervical with 52,38%. Most were macronodular with 85,71%. The response was good or excellent in 81,00% of cases with the first infiltration and rose to 95,00% with the second and third, as required. CONCLUSION. The treatment of lymphangiomas with bleomycin was very effective in the population studied.

Managing Recurrent Orbital Lymphangioma in a Pubertal Female with Negative Pressure Aspiration and Intralesional Bleomycin Injection: A Case Report.

INTRODUCTION: Management of orbital lymphangioma is challenging. Complete surgical excision is often impossible due to its infiltrative nature. Sclerosing agents have been used in its management with variable outcomes. We report a case of recurrent orbital lymphangioma managed with intralesional bleomycin. CASE: A 14-year-old female presented with proptosis of the right eye for two weeks. She had a similar history at five years of age for which she underwent surgical excision. We performed negative pressure aspiration using a 20-gauge angiocatheter, injected bleomycin, and left the cannula in situ for repeat aspiration to maintain cyst collapse. OBSERVATION: The lymphangioma regressed, and there was no recurrence at six months of follow-up. CONCLUSION: This report highlights the use of negative pressure aspiration and intralesional bleomycin injection by minimal intervention using angiocatheter in the successful management of orbital lymphangioma.

Bleomycin sclerotherapy in lymphangiomas of the head and neck region: a prospective study.

Intralesional sclerotherapy for lymphatic malformations (LMs) has become a modality of choice because of the high morbidity and recurrence rates with surgical excision. Traditionally, the macrocystic variant has shown good results with sclerotherapy. This prospective study was performed to evaluate the role of bleomycin sclerotherapy in the management of different radiological variants of LM. A total of 142 patients were included in this study. The lesions were classified as macrocystic, microcystic, or mixed LMs on the basis of ultrasonography. All patients were managed by intralesional injection of bleomycin and were recalled after 4 weeks for evaluation. Colour photographs of the patients were taken before the onset of treatment and at each monthly visit, and were utilized to assess the response. Following the second, third, and fourth doses, the response was better in patients with the macrocystic variant than in those with the other two variants. However, after the completion of six doses, 80.3% of patients with the macrocystic variant, 67.4% with the microcystic variant, and 71.4% with the mixed type had a complete response. There was no difference in the overall response between the three types (P=0.28). Oedema, erythema, and local induration with fever were the most common adverse effects and were more common in younger children.

[Acquired progressive lymphangioma in a 13-year-old boy]. / Erworbenes progressives Lymphangiom bei einem 13­jährigen Jungen.

Acquired tumors of lymphatic vessels are rare. Clinically, progressive lymphangioma usually appears as circumscribed plaques of small to medium size. In contrast, our case of a 13-year-old boy demonstrates a case of progressive lymphangioma with a solitary large indurated plaque. No extracutaneous manifestation was found. Systemic therapy with corticosteroids and methotrexate resulted in an improvement of the patient's condition. Dependent on clinical course and appearance of the disease, therapy with mTOR inhibitors may be considered as a therapeutic option.

New Treatment Option for Capillary Lymphangioma: Bleomycin-Based Electrochemotherapy of an Infant.

The treatment of microcystic and combined lymphangiomas, especially in the head and neck region, is still a challenge because the lymphangiomas do not respond to conventional therapies and their recurrence rate is high, regardless of the treatment choice. Complete surgical resection is the main treatment of lymphangiomas, but because of localization perioperative complications, such as bleeding, neural damage and airway obstruction are common disadvantages of this method. Bleomycin-based sclerotherapy is another common therapeutic approach, in which the lymphocysts are aspirated, and 25% to 50% of their volumes are replaced with a sclerotisant drug. This is an effective treatment in cases in which the vessels are large enough for an intravascular or intracystic injection, but because of the small size of vessels and cysts, the microcystic and combined lymphangiomas are not suitable for sclerotherapy. Delivery of drugs for treating sclerosis to endothelial cells can be achieved by electroporation (electrochemotherapy), even for capillary malformations. A congenital, rapidly growing combined lymphangioma of the left cervicofacial region was treated with one session of bleomycin-based electrochemotherapy. Seven months after treatment, the growth-corrected target volume decrease was 63% and the dislocation of the trachea and blood vessels previously observed had ceased. We suggest that bleomycin-based electrochemotherapy is a feasible alternative treatment option for capillary malformations.

Macrocystic Lymphangioma in Children Treated by Sclerotherapy With Bleomycin.

Although surgical operation is a commonly preferred method in lymphangiomas (LAs), there is a risk of vascular or nerve injury especially in macrocystic LA. Therefore, sclerotherapy would be more appropriate as the first treatment. The authors wanted to share the excellent results of intralesional bleomycin treatment in 3 patients with cervical macrocystic LA.

Malformación venolinfática orbitaria (linfangioma) resuelta con bleomicina intralesional / Orbital venous lymphatic malformation (lymphangioma) healed with intra-lesional bleomycin

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Management of a case of orbital lymphangioma presenting in adulthood with negative-pressure aspiration and bleomycin injection.

We hereby report a case of a 55-year-old woman, with complaints of sudden onset outward protrusion of left eye progressing over 2 months, along with pain and loss of vision. Visual acuity in the affected eye was light perception only. On imaging, a well-defined solitary cystic lesion was noted in the retrobulbar space, which showed no enhancement on contrast-enhanced MRI. We performed fluid aspiration from the cyst under negative pressure and injected bleomycin as a sclerosant, without attempting a surgical excision. The proptosis reduced visibly, and after a week, visual acuity improved to finger counting at 1 m. At the 6 months follow-up, the patient did not show any recurrence of proptosis. This report highlights the importance of sclerosant therapy without the need for surgical excision in managing macrocystic lymphangiomas in adult age group.

Interventions for orbital lymphangioma.

BACKGROUND: Orbital lymphangiomas are a subset of localized vascular and lymphatic malformations, which most commonly occur in the head and neck region. Orbital lymphangiomas typically present in the first decade of life with signs of ptosis, proptosis, restriction of ocular motility, compressive optic neuropathy, and disfigurement. Therefore, early and effective treatment is crucial to preserving vision. Due to proximity to vital structures, such as the globe, optic nerve, and extraocular muscles, treatment for these lesions is complicated and includes a large array of approaches including observation, sclerotherapy, systemic therapy, and surgical excision. Of these options, there is no clear gold standard of treatment. OBJECTIVES: To assess the evidence supporting medical and surgical interventions for the reduction/treatment of orbital lymphangiomas in children and young adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 5); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 May 2018. SELECTION CRITERIA: We planned to include randomized controlled trials (RCTs) comparing at least two of the following interventions with each other for the treatment of orbital lymphangiomas: observation; sildenafil therapy; sirolimus therapy; sclerotherapy; surgery (partial or complete resection). We planned to include trials that enrolled children and adults up to 32 years of age, based on a prior clinical trial protocol. There were no restrictions regarding location or demographic factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles, abstracts, and full articles to assess their suitability for inclusion in this review. No risk of bias or data extraction was performed because we did not find any trials for inclusion. If there had been RCTs, two authors would have assessed the risk of bias and abstracted data independently with discrepancies being settled by consensus or consultation with a third review author. MAIN RESULTS: There were no RCTs that compared any two of the mentioned interventions (medical or surgical) for treating orbital lymphangiomas in children and young adults. AUTHORS' CONCLUSIONS: Currently, there are no published RCTs of orbital lymphangioma treatments. Without these types of studies, conclusions cannot be drawn regarding the effectiveness of the medical and surgical treatment options for patients with orbital lymphangiomas. The presence of only case reports and case series on orbital lymphangiomas makes it clear that RCTs are needed to address the differences between these options and help guide treatment plans. Such trials would ideally compare outcomes between individuals randomized to one of the following treatment options: observation, sclerotherapy, systemic sirolimus therapy, systemic sildenafil therapy, and surgical excision.

Signaling pathways and inhibitors of cells from patients with kaposiform lymphangiomatosis.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. PROCEDURE: Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. RESULTS: Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK-1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K-AKT and MAPK-ERK-1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K-AKT-mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. CONCLUSIONS: Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.