sirolimus and Lymphatic-Abnormalities

This PRISMA-compliant systematic review aimed to assess risks and benefits of sirolimus treatment for paediatric lymphatic malformations by focusing not only on treatment efficacy but also on possible treatment-related adverse events, and treatment combinations with other techniques.. Search criteria were applied to MEDLINE, Embase, Web of Science, Scopus, Cochrane Library, and ClinicalTrials.gov databases and included all studies published up to March 2022 reporting paediatric lymphatic malformations treated with sirolimus. We selected all original studies that included treatment outcomes. After the removal of duplicates, selection of abstracts and full-text articles, and quality assessment, we reviewed eligible articles for patient demographics, lymphatic malformation type, size or stage, site, clinical response rates, sirolimus administration route and dose, related adverse events, follow-up time, and concurrent treatments.. Despite promising results for sirolimus treatment in lymphatic malformation, the efficacy and safety profile of remains unclear due to the lack of high-quality studies. Systematic reporting of known side effects, especially in younger children, should assist clinicians in minimising treatment-associated risks. At the same time, we advocate for prospective multicentre studies with minimum reporting standards to facilitate improved candidate selection.

Topics: Child; Head; Humans; Lymphatic Abnormalities; Neck; Prospective Studies; Sirolimus; Treatment Outcome; Vascular Malformations

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.. 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.. 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.. 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.

Topics: Child; Humans; Lymphangioma; Lymphatic Abnormalities; Pediatrics; Sclerotherapy; Sirolimus

Children with extensive lymphatic malformations of the head and neck often suffer from functional impairment and aesthetic deformity which significantly affect the quality of life and may be life-threatening. Treatment with sirolimus has the potential to improve symptoms and downsize lymphatic malformations. This systematic review summarizes the current information about sirolimus treatment of lymphatic malformations of the head and neck in children, its efficacy and side effects.. A systematic search of the literature regarding studies on sirolimus treatment of children with lymphatic malformations of the head and neck was performed in PubMed, Embase, and Google Scholar up to July 2021 with the search terms "lymphatic malformation", "lymphangioma", "cystic hygroma", "low-flow malformation", "sirolimus", "rapamycin", "mTOR inhibitor" and "children".. Sirolimus could be an effective treatment for children with large complicated lymphatic malformations of the head and neck. As not all patients will benefit from treatment, the decision to treat sirolimus should be made by a multidisciplinary team.

Topics: Head; Humans; Infant, Newborn; Lymphatic Abnormalities; Neck; Quality of Life; Sirolimus; Treatment Outcome; Vascular Malformations

Topics: Bone Diseases; Female; Humans; Lymphatic Abnormalities; Pamidronate; Sirolimus; Vincristine

Lymphatic malformations (LM) are common congenital vascular lesions, most often diagnosed at birth. They deform local anatomy and can be life-threatening if they compress the aerodigestive tract or other vital structures. Significant progress has been made in the treatment of LMs in the past 20 years. We conducted a systematic review of the literature on the management of LMs.. On September 21, 2020, we searched PubMed/MEDLINE for studies published from 2000 to 2020 reporting outcomes of invasive and pharmacologic treatment of LMs.. A total of 251 studies met the eligibility criteria. Surgery has continued to be a mainstay in the management of LMs, especially in the treatment of microcystic and mixed lesions. Sclerotherapy has emerged as a first-line treatment of macrocystic LMs and as an adjunctive therapy used in combination with surgery for other lesions. Sirolimus, a strong inhibitor of mTOR (mechanistic target of rapamycin), has shown tremendous promise in the treatment of LMs, as both an oral and a topical agent. Recent investigations have shown the potential of targeted small molecule modulators of cellular pathways in the treatment of LMs.. Multiple invasive and pharmacologic therapies have been shown to be effective in the treatment of LMs. Future research should focus on rigorous, prospective comparisons of these treatment modalities.

Topics: Class I Phosphatidylinositol 3-Kinases; Humans; Lymphatic Abnormalities; MTOR Inhibitors; Sclerosing Solutions; Sclerotherapy; Sirolimus

Extensive lymphatic malformations are low-flow vascular malformations that can cause devastating complications. Treatment of these malformations is challenging. This systematic review presents current use of sirolimus in patients with extensive lymphatic malformations.. MEDLINE and Google scholar search was conducted for studies on sirolimus treatment of lymphatic malformations up to July 2017. Search items included "lymphatic malformation," "lymphangioma," "cystic hygroma," "vascular malformation," "low-flow malformation," "sirolimus," "rapamycin," and "mTOR inhibitor.". Twenty studies, including 71 patients receiving sirolimus, were included into this review. Forty-five patients had lymphatic malformations, eight patients venolymphatic malformations, and 19 patients capillary-lymphatico-venous malformations. Sirolimus led to a partial remission of disease in 60 patients, three patients had a progressive disease, and the outcome of eight patients was not reported. Dosing, target trough level, and duration of treatment differed between the studies. Common adverse effects were hyperlipidemia and neutropenia.. Available literature indicated that sirolimus therapy might be effective for lymphatic malformations. However, further randomized controlled studies are required to analyze the efficacy and long-term adverse events and to clarify the potential role for sirolimus in the management of lymphatic malformations.

Topics: Disease Progression; Female; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Remission Induction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Vascular malformations of the head and neck are complex lesions that are notoriously difficult to manage. Treatment of these lesions often requires a multispecialty and multimodal approach. In the modern era of evidence-based medicine, it has become imperative for clinicians to incorporate evidence-based treatment algorithms into their everyday practices. With general widespread inundation of the literature with levels IV and V clinical evidence, however, it is often difficult to draw meaningful conclusions that can be practically applied to the clinical question at hand. When asking how best to manage the most common vascular malformations, we are faced with this large volume of lower level studies conducted in drastically different ways without consistency in outcomes reporting, thus making direct comparison nearly impossible. Furthermore, much of the evidence shows mixed results, adding to confusion over what the optimal evidence-based treatment approaches truly are. In attempt to derive consensus from available literature discussing the management of vascular malformations, we reviewed the current literature detailing modern-day treatment approaches for lymphatic malformations, venous malformations, and arteriovenous malformations of the head and neck.

Topics: Ablation Techniques; Arteriovenous Malformations; Embolization, Therapeutic; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Laser Therapy; Lymphatic Abnormalities; Lymphatic Vessels; Phosphodiesterase 5 Inhibitors; Sclerotherapy; Sildenafil Citrate; Sirolimus; Vascular Malformations; Veins; Watchful Waiting

Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations presenting as clusters of cysts filled with lymph fluid or blood. Even small well-limited lesions can be responsible for a heavy burden, inducing pain, aesthetic prejudice, or oozing, bleeding, infections. The natural history of LMLMs is progressive worsening punctuated by acute flares. Therapeutic options include surgery, laser excision, and radiofrequency ablation but all are potentially detrimental and expose to local relapse. Therefore, the management frequently relies on a "watchful waiting" approach. In complicated LMLMs, treatment with oral sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is often used. Topical applications of sirolimus on the buccal mucosae have been reported in other oral diseases with good tolerance and none to slight detectable blood sirolimus concentrations. We aim to evaluate the efficacy and safety of a 1 mg/mL sirolimus solution applied once daily on LMLM of any stage in children and adults after 4, 8, 12, 16, 20, and 24 weeks of treatment compared to usual care (no treatment).. This is a randomized, multicentric study using an individually randomized stepped-wedge design over 24 weeks to evaluate topical application of a 1 mg/mL sirolimus solution once daily, on LMLM, versus usual care (no treatment), the control condition. Participants begin with an observational period and later switch to the intervention at a randomized time (week 0, 4, 8, or 12). Visits occur every 4 weeks, either in the study center or by teleconsulting. The primary outcome will be the evaluation of global severity of the LMLM on monthly standardized photographs by 3 independent blinded experts using the physical global assessment (PGA) 0 to 5 scale. Secondary outcomes will include lesion size measurement and quality of life assessment, investigator, and patient-assessed global disease and specific symptoms (oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain, and global discomfort) assessment. A biological monitoring will be performed including residual blood sirolimus concentration and usual laboratory parameters.. Given the disappointing state of current treatment options in LMLMs, topical sirolimus could become firstline therapy in treating LMLMs if its efficacy and safety were to be demonstrated.. ClinicalTrials.gov NCT04128722 . Registered on 24 September 2019. EudraCT: EUCTR2019-001530-33-FR Sponsor (University Hospital Center of Tours - CHRU Tours): DR190041-TOPGUN French regulatory authorities: ID RCB: 2019-001530-33.

Topics: Adult; Child; Cysts; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Pain; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome

Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking.. To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment.. This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020.. Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient.. The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety.. Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]).. This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms.. ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.

Topics: Adolescent; Child; Female; Humans; Lymphatic Abnormalities; Quality of Life; Sirolimus; Treatment Outcome; Vascular Malformations

To evaluate the efficacy of initial sirolimus therapy in the treatment of intractable head and neck lymphatic malformations (LMs) in children.. Prospective open-label study.. In this study, Twenty-seven children diagnosed with LMs were given oral sirolimus as primary treatment over a minimum 6-month trial. The major parameter to evaluate therapeutic outcome was percentage of lesion volume change compared with baseline. Average serum sirolimus concentrations, and adverse side effects, were monitored throughout the study period.. Fifteen girls and twelve boys, average age 27 months (16 days-171 months), constitute the study group. Treatment was deemed effective for twenty-three participants, judged as fair in seven, good in nine, and excellent in seven. Two patients had minimal improvement, and two had increased volume to some degree. Effectiveness differed among LMs subtypes with responsiveness of macrocystic LMs exceeding that of microcystic LMs (P < .05). Adverse drug reactions totaled 27 events in ten patients, the majority being mild with upper respiratory infections being most common.. Sirolimus as initial therapy is effective in decreasing lesion volume in intractable LMs in head and neck region, especially in macrocystic subtypes. Although most cases cannot be completely cured, side effects are few and tolerable.. 4 Laryngoscope, 131:1902-1908, 2021.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Drug Monitoring; Female; Head; Humans; Infant; Infant, Newborn; Lymphatic Abnormalities; Male; Neck; Prospective Studies; Sirolimus; Treatment Outcome

Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults.. This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm. For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment.. ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018-001359-11.

Topics: Administration, Cutaneous; Adolescent; Adult; Child; Clinical Trials, Phase II as Topic; Dermatologic Agents; Double-Blind Method; France; Humans; Lymphangiectasis; Lymphatic Abnormalities; Multicenter Studies as Topic; Quality of Life; Randomized Controlled Trials as Topic; Sirolimus; Skin Diseases; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies.. Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed.. Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment.. Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.

Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Infant, Newborn; Lymphatic Abnormalities; Male; Osteolysis, Essential; Prognosis; Prospective Studies; Retrospective Studies; Sirolimus; Young Adult

Lymphatic malformations (LMs) are uncommon congenital abnormalities of the lymphatic system. As more than half of these lesions develop in the head and neck, LMs can be life-threatening if associated with airway involvement. LMs necessitate a multidisciplinary treatment approach, frequently including surgery and sclerotherapy. We present a case report of a 32-week pre-term male infant with a massive cervicofacial LM necessitating delivery via ex-utero intrapartum treatment (EXIT). The patient was treated with numerous rounds of sclerotherapy, systemic sirolimus, and surgical debulking, but ultimately died at 4 months of age due to acute pulmonary hemorrhage, which may have been related to sirolimus due to the absence of any other associable organ involvement or derangement. We document the patient's clinical course and treatment regimen, highlighting the myriad modalities employed to treat these challenging lesions, and describe a potentially lethal complication of sirolimus therapy not previously described in the treatment of pediatric LM.

Topics: Child; Head; Humans; Infant; Lymphangioma, Cystic; Lymphatic Abnormalities; Male; Neck; Retrospective Studies; Sclerotherapy; Sirolimus; Treatment Outcome

Topics: Child; Humans; Immunosuppressive Agents; Lymphangioma; Lymphatic Abnormalities; Sirolimus

To explore the differences in the efficacy and safety of oral sirolimus and sildenafil in the treatment of pediatric intractable lymphatic malformations (LMs).. From January 2014 to May 2022, we retrospectively enrolled children with intractable LMs treated with oral drugs (sirolimus or sildenafil) and divided the patients into sirolimus and sildenafil groups from Beijing Children's Hospital (BCH). Clinical features, treatment, and follow-up data were collected and analyzed. The indicators were the ratio of reduction in lesion volume pre and posttreatment, the number of patients with improved clinical symptoms, and adverse reactions to the two drugs.. Twenty-four children in the sildenafil group and 31 children in the sirolimus group were included in the present study. The effective rate in the sildenafil group was 54.2% (13/24), with a median lesion volume reduction ratio of 0.32 (-0.23, 0.89) and clinical symptoms improved in 19 patients (79.2%). On the contrary, the effective rate in the sirolimus group was 93.5% (29/31), with a median lesion volume reduction ratio of 0.68 (0.34, 0.96), and clinical symptoms improved in 30 patients (96.8%). There were significant differences (p < 0.05) between the two groups. Regarding safety, four patients in the sildenafil group and 23 patients in the sirolimus group with mild adverse reactions were reported.. Both sildenafil and sirolimus can reduce the volume of LMs and improve clinical symptoms in partial patients with intractable LMs. Sirolimus is more effective than sildenafil and the adverse reactions associated with both drugs are mild and controllable.. III Laryngoscope, 133:3192-3199, 2023.

Topics: Child; Humans; Lymphatic Abnormalities; Retrospective Studies; Sildenafil Citrate; Sirolimus; Treatment Outcome; Vascular Malformations

Topics: Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Sirolimus; Skin Diseases, Vascular

The cervicofacial lymphatic malformations (LMs) often have poor outcomes due to their microcystic component and diffuse infiltration. Mostly, traditional treatments are inadequate for these refractory cases. Recent researches have shown that sirolimus is effective in the treatment of complicated LMs, however, there is still no standard strategy.. To evaluate the efficacy and safety of intermittent oral sirolimus in treating refractory cervicofacial LMs as a second-line treatment.. Fifteen pediatric patients of refractory cervicofacial LMs were retrospectively analyzed in this study. All the cases had received traditional therapy before, but could not completely control the symptoms and eliminate lesions. As a remedy, sirolimus was then proceeded with an intermittent administration regimen, that is 3 continuous months as a course and started the next course after 1 month interval. The clinical characteristics, imaging data of patients, the changes in the signs and symptoms observed, and associated adverse effects were collected and analyzed.. The patients initiated sirolimus therapy at the average age of 2.3 years (range 28 days-8 years 9 months). At the end point of the study, 2 patients remained on sirolimus in continuous courses of treatment. Of 13 patients who withdrawn therapy, 4 had restarted due to recurrence of symptoms and re-expansion of LMs. All patients demonstrated reduction in residual LMs and complete disappearance of symptoms during treatment, and 2 patients with complete resolution on imaging. Toxicity was tolerant in this series. There was no patient develop opportunistic or systemic bacterial infection.. Sirolimus is commended as a second-line treatment to treat intractable cervicofacial LMs after failure of traditional therapy. The intermittent administration regimen is efficacious to completely control symptoms and partially reduce residual lesions with good tolerance and limited side effects.

Topics: Child; Child, Preschool; Humans; Lymphangioma, Cystic; Lymphatic Abnormalities; Retrospective Studies; Sirolimus; Treatment Outcome

Chylothorax can be a presenting symptom of complex lymphatic anomaly in children and is associated with significant respiratory morbidity. Historically, the traditional pharmacological treatment has been octreotide. There are several treatments that have been utilized in the past few years including sirolimus; however, data regarding their efficacy and outcomes is limited. Furthermore, sirolimus has proven efficacy in complex vascular malformations, and hence, its utility/efficacy in infantile primary chylous effusions warrants further investigation.. In this retrospective study at Texas Children's Hospital, data were extracted for all infants with chylothorax who were treated with sirolimus between 2009 and 2020. Details regarding underlying diagnosis, comorbidities, and number of days from sirolimus initiation to resolution of effusion were collected.. Initially a total of 12 infants were identified. Among them, seven patients had complete data and were included in the study. Reasons for chylous effusions include presumed complex lymphatic anomaly, generalized lymphatic anomaly, and complex congenital lymphatic anomaly. The mean duration of sirolimus treatment needed for chest tube removal was 16 days, with a median of 19 days and range of 7-22 days. No patients had progression of effusions while on sirolimus.. With close monitoring, sirolimus appears to be an effective therapy for pediatric lymphatic effusions even in critically ill infants. The study also demonstrates shorter duration of chest tube requirement after initiation of sirolimus compared to previous studies. Larger multi-institutional studies are needed to further support our findings.

Topics: Child; Chylothorax; Critical Illness; Humans; Infant; Lymphatic Abnormalities; Octreotide; Pleural Effusion; Retrospective Studies; Sirolimus

Topics: Humans; Infant, Newborn; Lymphatic Abnormalities; Sirolimus; Treatment Outcome

Abdominal lymphatic malformations (LM) have been historically managed with surgical resection; however, sclerotherapy and sirolimus have emerged as effective therapies. The purpose of our study is to evaluate our institutional change in management and outcomes for abdominal LM over the past decade.. A retrospective cohort study was performed for all children with an abdominal LM managed at our multidisciplinary Vascular Anomalies Center from 2011 to 2020. Patient demographics, symptoms, treatment, treatment response, and complications were analyzed with descriptive statistics.. Twenty-nine patients with abdominal LM were identified with a median age at treatment of 6 y (interquartile range 3-14). A majority of lesions were identified as macrocystic (n = 18, 62%). The most common intervention was surgery alone (n = 14, 48%) followed by sirolimus alone (n = 4, 14%), and sclerotherapy + sirolimus (n = 4, 14%). Five patients were observed due to lack of symptoms at presentation. Prior to 2017, 91% (10/11) of LM were treated with surgery alone. Following 2017, only 31% (4/13) were treated with surgery alone. Sixty-seven percent (16/24) of treated patients had >95% reduction in LM maximum diameter. A majority of patients (23/24) who received treatment had improvement or resolution of symptoms at median 9-mo follow-up. Only three patients had post-treatment complications, including a drain site infection, small bowel obstruction, and an aspiration event. Complications only occurred after sclerotherapy sessions.. Over the study period, our institution has transitioned to initial management of symptomatic abdominal LM with sclerotherapy and/or sirolimus with almost all treated patients having excellent or satisfactory treatment response. Post-treatment complications were rare.

Topics: Child; Humans; Infant; Lymphatic Abnormalities; Retrospective Studies; Sclerotherapy; Sirolimus; Treatment Outcome

This case report describes a 17-year-old male patient with frog spawn–like vesicles around the urethra.

Topics: Female; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Sirolimus; Urethra; Vulva

淋巴管畸形（lymphatic malformations，LM）是儿童的常见疾病，其治疗手段包括硬化剂注射、手术、射频消融等。但是，对于弥漫性浸润式生长的难治性LM，传统的局部治疗手段无法取得良好的疗效，是临床治疗的重大挑战。近年来的基础研究发现，LM组织中的内皮细胞发生体细胞基因突变导致PI3K/AKT/mTOR通路持续激活，是LM发生发展的重要原因，这为靶向该通路的抑制治疗提供了分子基础。其中，西罗莫司（mTOR抑制剂）治疗LM是目前的研究热点，本文就西罗莫司治疗LM的最新研究进展进行综述。.

Topics: Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Sirolimus; Treatment Outcome

To describe the effects of oral sirolimus administered before and after surgical resection of slow-flow vascular malformations of the scrotum in pediatric patients.. Retrospective review of 3 patients presenting with complex lymphatic-venous malformations of the scrotum who received adjuvant oral sirolimus 3 months before and 3 months after surgical resection. Demographic data, clinical course, imaging findings, and management strategies were reviewed for each patient.. In each of the 3 patients, there was a significant volume reduction of the lesion within the 3 months after initial dose of sirolimus. Scarce lymphatic leakage during and after surgery was reported, associated with an adequate wound healing. Two years after the last postsurgical dose of sirolimus, all patients remain asymptomatic without any lymphatic leakage or lesion recurrence.. Combined lymphatic-venous vascular malformations of the male genitalia are rare but associated with high morbidity and challenging treatment options. Pre- and postsurgical adjuvant treatment with oral sirolimus seems to be a promising therapeutic option that provides reduction of the lesion size before surgery and improvement of postsurgical recovery and wound healing.

Topics: Administration, Oral; Child; Child, Preschool; Humans; Infant; Lymphatic Abnormalities; Male; Postoperative Care; Premedication; Retrospective Studies; Scrotum; Sirolimus; Vascular Malformations; Wound Healing

Sirolimus has become a pillar in the treatment of vascular anomalies due to its inhibition of the mammalian target of rapamycin (mTOR). Adverse effects include metabolic and hematologic disorders among others, although menstrual disorders have not been well described.. Retrospective review of patients with vascular anomalies on sirolimus treatment was performed. Patients presenting menstrual alterations were included.. One hundred and thirty-six patients with vascular anomalies on treatment with sirolimus were reviewed, finding seven women out of 74 (9.4%) who presented menstrual alterations attributable to the treatment. These seven patients presented with different vascular malformations and three showed pathogenic variants in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) in affected tissue. Partial response in six and stability in one patient was obtained after treatment, administered for an average of 27.5 months (6-48). Five patients have completed treatment and two patients continue on after 12 and 15 months, respectively. All patients reported regular menstrual cycles prior to sirolimus treatment. One patient presented with amenorrhea for 4 months after treatment initiation that later spontaneously resolved. The other six patients presented with hypermenorrhea, four of them associating metrorrhagia. Most patients presented with mild menstrual alterations, without needing dose reduction or withdrawal, although one discontinued sirolimus due to hypermenorrhea, metrorrhagia, and hematuria. After sirolimus withdrawal, regular menstrual cycles were restored in five patients.. Sirolimus treatment can produce menstrual disorders as adverse effects. Although mild and reversible upon dose reduction or cessation of treatment, patients and physicians should be aware on this potential side effect.

Topics: Antibiotics, Antineoplastic; Female; Follow-Up Studies; Humans; Lymphatic Abnormalities; Menstruation Disturbances; Prognosis; Retrospective Studies; Sirolimus; Vascular Malformations

Clinical studies have shown low toxicity and a favorable safety profile for sirolimus in vascular anomalies. Here, we describe severe adverse events (SAEs) observed during "off-label use" for vascular anomalies.. We performed a retrospective, multicenter chart review for SAEs during "off-label" sirolimus therapy for vascular anomalies and analyzed these cases by a predesigned workflow.. We identified 17 SAEs in 14 patients diagnosed with generalized lymphatic anomaly (n = 4), Gorham-Stout disease (n = 2), central conducting lymphatic anomaly (n = 1), lymphatic malformation (n = 4), tufted angioma (n = 1), kaposiform hemangioendothelioma (n = 1), and venous malformation in a patient with CLOVES syndrome (n = 1). Three patients presented two SAEs each. The age at initiation of sirolimus therapy was under 2 years (n = 5), 2-6 years (n = 5), and older than 12 years (n = 4). SAEs occurred during the first 3 months of sirolimus therapy (n = 7), between 3 and 12 months (n = 7) and after 1 year of therapy (n = 3). The most frequent SAE was viral pneumonia (n = 8) resulting in one death due to a metapneumovirus infection in a 3 months old and a generalized adenovirus infection in a 28-month-old child. Sirolimus blood level at the time of SAEs ranged between 2.7 and 21 ng/L. Five patients were on antibiotic prophylaxis.. Most SAEs are observed in the first year of sirolimus therapy; however, SAEs can also occur after a longer treatment period. SAEs are potentially life threatening, especially in early infancy. Presence of other risk factors, that is, underlying vascular anomaly or immune status, may contribute to the risk of SAEs. Sirolimus is an important therapeutic option for vascular anomalies, but patients and physicians need to be aware that adequate monitoring is necessary, especially in patients with complex lymphatic anomalies that are overrepresented in our cohort of SAEs.

Topics: Child, Preschool; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Lymphatic Abnormalities; Off-Label Use; Retrospective Studies; Sirolimus; Vascular Malformations

WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?: Fetal lymphatic malformations (LMs) can be detected on prenatal ultrasound and until recently, therapeutic options were limited. Recently the mammalian target of rapamycin inhibitor rapamycin has emerged as a safe, effective therapy for children with LMs and multiple studies have demonstrated improved efficacy if started early. WHAT DOES THIS STUDY ADD?: We report the first in-utero therapy with rapamycin for a rapidly enlarging, obstructive, fetal cervical LM. Fetal therapy with rapamycin was safe and effective in managing this severe malformation, despite rapamycin being started only in the last 6.5 weeks of pregnancy. We speculate that had rapamycin been commenced earlier, the reduction in mass size might have been even greater.

Topics: Adult; Anti-Bacterial Agents; Female; Fetal Therapies; Humans; Lymphatic Abnormalities; Pregnancy; Sirolimus; Ultrasonography, Prenatal

Kaposiform lymphangiomatosis (KLA), which is a new subtype of generalized lymphatic anomaly, is a rare disease with a poor prognosis. Currently, there is no standard treatment due to the poor understanding of KLA. Sirolimus, which is an inhibitor of mammalian target of rapamycin, has been shown to have promising potential in the treatment of complicated vascular anomalies. The aim of this study was to introduce the use of sirolimus for the treatment of KLA and to highlight the challenges of managing this refractory disease.. We reported seven patients with KLA who received sirolimus therapy in our center. Combined with previously reported cases, 58.3% achieved a partial response, 25.0% had stable disease, and 16.7% experienced disease progression. No severe sirolimus-related adverse events occurred during treatment.. This study suggests that sirolimus is currently an option for the treatment of KLA, and it is hoped that more specific therapies will be developed in the future. Rapid advances in basic science and clinical practice may facilitate the development of important new treatments for KLA.

Topics: Humans; Lymphangioleiomyomatosis; Lymphatic Abnormalities; Sirolimus; Vascular Malformations

Mammalian target of rapamycin (mTOR) inhibitors have been shown to have excellent effects in the management of kaposiform hemangioendothelioma (KHE); however, the mechanism of action is unclear. This study identified the expressions of mTOR pathway-related proteins in different vascular tumors to provide insight into the pathogenesis of KHE.. We retrospectively reviewed the pathologic specimens of 30 patients (KHE, 15; tufted angioma [TA], 5; infantile hemangioma [IH], 5; and lymphatic malformation [LM], 5). The immunohistochemical expression of mTOR-related proteins tuberous sclerosis complex 2 (TSC2), phosphatase and tensin homologue (PTEN), phosphorylated eukaryotic translation initiation factor 4E binding protein 1 (p-4EBP1), phosphorylated mTOR (p-mTOR), and phosphorylated ribosomal protein S6 kinase B1 (p-P70S6K) were analyzed using Image-Pro Plus software. KHE had the following pattern of expression in the spindle vascular endothelial cells: TSC2 (-); PTEN (-); p-4EBP1 (+); p-mTOR (+); and p-P70S6K (+).. All 3 patients treated with sirolimus had good responses. The TA results were similar to KHE with no significant differences (p-4EBP1: p = 0.0687; p-mTOR: p = 0.0832). The expressions of TSC2, PTEN, p-4EBP1, p-mTOR, and p-P70S6K were negative or weakly positive in IH with a statistically significant difference compared to KHE (p-4EBP1: p < 0.001; p-mTOR: p < 0.001; p-P70S6K: p < 0.001). LM had no significant differences when compared to KHE.. The absence of TSC2 and PTEN caused abnormal activation of the mTOR signaling pathway and may be involved in the pathogenesis of KHE. The expression of mTOR-related proteins in TA and LM was similar to KHE, unlike IH. The KHE pattern of expression [PTEN (-), TSC2 (-), p-mTOR (+), p-P70S6K (+), and p-4EBP1 (+)] suggested that sirolimus may be a good therapeutic choice.

Topics: Antineoplastic Agents; Endothelial Cells; Hemangioendothelioma; Hemangioma; Humans; Immunohistochemistry; Kasabach-Merritt Syndrome; Lymphatic Abnormalities; Retrospective Studies; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Vascular anomalies (VA), characterized by the abnormal development or growth of blood and/or lymphatic vessels, encompasses a spectrum of conditions with a range of symptoms and complications. VA are frequently associated with cutaneous complications that can cause significant morbidity. Systemic sirolimus has previously been shown to be effective in the treatment of complicated VA. There are limited studies to date on the use of topical sirolimus for the treatment of cutaneous manifestations of VA.. Retrospective review of medical records of pediatric patients with VA treated with topical sirolimus at a single quaternary pediatric institution. Response was determined by clinical subjective and objective measures of improvement.. Twenty-three patients with cutaneous VA manifestations were treated with topical sirolimus. Median age was 14 (range 4-27 years). The main indication for treatment was complication of lymphatic blebbing (82%, n = 19) including lymphatic fluid leakage, bleeding, pain, pruritus, swelling, or recurrent infection. Treatment course ranged from 109 to 1424 days with median of 622 days. No major side effects were reported. Eighty-six percent of patients (n = 20) had subjective or objective improvement of cutaneous lesions. Lymphatic blebbing complications improved in 90% (n = 17) of individuals. Eighty-two percent (n = 14) of patients not receiving concurrent systemic sirolimus demonstrated improvement with topical therapy. One patient electively stopped treatment due to pruritus and burning sensation.. Topical sirolimus appears to be a beneficial therapy for lymphatic blebbing associated with lymphatic malformations or mixed malformations with a lymphatic component, although benefit in other VA remains unclear. Topical sirolimus was well-tolerated with minimal side effects.

Topics: Administration, Topical; Adolescent; Adult; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Retrospective Studies; Sirolimus; Skin Diseases; Vascular Malformations; Young Adult

Systemic sirolimus (rapamycin) has recently been found effective in treating complex vascular anomalies by reducing the size and associated complications. Many vascular anomalies have a cutaneous component, and thus, we sought to determine whether topical administration of sirolimus may be an effective therapy, as data on the use of topical sirolimus are limited.. We reviewed the efficacy and tolerability of topical formulations of sirolimus in the treatment of various simple and combined vascular malformations and tumors.. Eighteen patients with any vascular anomaly treated exclusively with topical sirolimus were retrospectively reviewed.. Eleven patients had combined venous lymphatic malformations, three had tufted angiomas, two had a lymphatic malformation, one had a venous malformation, and one had a verrucous venous malformation. All (100%) patients reported some degree of improvement and 50% of patients reported marked improvement in one or more symptoms, most commonly blebs and lymphatic drainage, and bleeding.. The retrospective nature, small number of patients, and differences in topical preparations limit the broad application of the results.. Topical sirolimus appears to be a safe and useful non-invasive therapy that is well-tolerated in the treatment of the cutaneous portion of a variety of vascular anomalies.

Topics: Administration, Topical; Adolescent; Adult; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Infant; Lymphatic Abnormalities; Male; Retrospective Studies; Sirolimus; Treatment Outcome; Vascular Malformations; Young Adult

Lymphatic malformations are common congenital vascular lesions. Neither surgical resection nor other surgical treatments have been found to be effective for invasive cases. Recent research has suggested that sirolimus is effective in treating complex lymphatic malformations (LMs). We aimed to evaluate the effectiveness and safety of oral sirolimus for children living with LMs in our hospital.. During the follow-up period, blood, liver and kidney function as well as disseminated intravascular coagulation was regularly reviewed in all 56 children. Enhanced MRI was regularly performed to evaluate therapeutic effects. Total effective rate (complete response or partial response) of LMs was 89.3% (50/56). No serious adverse reactions were found.. This study suggests that sirolimus is effective and tolerable for decreasing lesions in children with complex LMs, leading to fewer and more tolerable side effects. There is no need to pursue an excision rate to reduce unnecessary operative complications since adjuvant sirolimus therapy modifies the complex LMs clinical appearance and alleviates their symptoms.. Clinical research.. Level IV.

Topics: Child; China; Humans; Infant, Newborn; Lymphatic Abnormalities; Magnetic Resonance Imaging; Sirolimus; Treatment Outcome; Vascular Malformations

Sirolimus mTOR inhibitor represents a major advance in the treatment of patients with complicated vascular abnormalities. The objective of this study was to present our series of pediatric patients with vascular abnormalities treated with oral sirolimus, and to conduct a review of the relevant literature.. A retrospective analysis of patients with complicated vascular abnormalities treated with oral sirolimus in our healthcare facility from 2016 was carried out. Initial dosage was 0.8 mg/m2 every 12 hours, and therapeutic range was 5-15 ng/ml. All patients received trimethoprim-sulfamethoxazole prophylaxis.. 6 children -3 boys and 3 girls- with a mean age of 9.5 years at treatment initiation were included. 3 of them had head and neck lymphatic malformation, 2 had lower limb venous malformation, and 1 had combined lymphatic-venous malformation at the thoracoabdominal level. They all had received multiple previous treatments without improvement. Following sirolimus initiation, 5 patients had clinical improvement (mean time: 3.6 months) and 4 had radiological improvement (mean time: 6.6 months). Mild and transitory adverse effects were noted in the 3 cases. Today, 5 patients remain under treatment.. Oral sirolimus is an effective and safe treatment in patients with complicated vascular abnormalities. Our results support sirolimus use in lymphatic and venous malformations in which previous treatments have failed, with a good symptomatic and, to a lesser extent, radiological response.. El uso del inhibidor mTOR sirolimus ha supuesto un avance en el tratamiento de pacientes con anomalías vasculares complicadas. El objetivo de este estudio es presentar nuestra serie de pacientes pediátricos con anomalías vasculares tratados con sirolimus oral y hacer una revisión de la literatura al respecto.. Se realizó un análisis retrospectivo de los pacientes con anomalías vasculares complicadas tratados con sirolimus oral en nuestro centro desde el año 2016. La dosis inicial utilizada fue de 0,8 mg/m2 cada 12 horas y el rango terapéutico de 5-15 ng/ml. Todos los pacientes recibieron profilaxis con trimetoprim-sulfametoxazol.. Se incluyeron seis niños, tres varones y tres mujeres, con una edad media al inicio del tratamiento de 9,5 años. Tres presentaban una malformación linfática en cabeza y cuello, dos una malformación venosa en miembro inferior y la última una malformación combinada linfática-venosa a nivel toracoabdominal. Todos habían recibido múltiples tratamientos previos sin mejoría. Tras el inicio de sirolimus, cinco pacientes mejoraron clínicamente (tiempo medio 3,6 meses) y cuatro radiológicamente (tiempo medio 6,6 meses). Se registraron efectos adversos leves y transitorios en tres casos. Actualmente, cinco pacientes continúan con el tratamiento.. El sirolimus oral es un tratamiento eficaz y seguro en pacientes con anomalías vasculares complicadas. Nuestros resultados apoyan su uso en malformaciones linfáticas y venosas en las que han fracasado otros tratamientos, presentando buenas respuestas sintomáticas y, en menor medida, radiológicas.

Topics: Administration, Oral; Adolescent; Child; Child, Preschool; Female; Humans; Lymphatic Abnormalities; Male; Retrospective Studies; Sirolimus; Treatment Outcome; Vascular Malformations

The superficial lymphatic component of vascular malformations poses a significant treatment challenge. It is responsible for the majority of symptoms presented, and to date, there is no consensus regarding treatment.. To evaluate the effectiveness of topical rapamycin in treating superficial lymphatic malformations (LM).. A case series study was performed of patients with superficial LM, treated with topical rapamycin. The clinical characteristics of patients and the concentration and application mode of the drug were recorded. The changes in the signs and symptoms observed and associated adverse effects were noted and analyzed.. The study population consisted of 11 patients of an average age of 10.5 years. All were treated with topical rapamycin: 6 patients with a 1% concentration, 1 with a 0.8% concentration, and 4 with a 0.4% concentration. Changes in the clinical appearance of the lesions were observed in all patients. The associated symptoms, present in 9 of 11 patients, improved in every case. The mean follow-up time was 16.1 months.. This study is retrospective, with a small sample size and considerable heterogeneity of lesions and treatment approaches.. Treatment with topical rapamycin modifies the clinical appearance and alleviates symptoms of superficial LM.

Topics: Administration, Topical; Adolescent; Child; Child, Preschool; Cohort Studies; Female; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Prognosis; Retrospective Studies; Severity of Illness Index; Sirolimus; Treatment Outcome

Topics: Administration, Topical; Adolescent; Buttocks; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Sirolimus

Topics: Female; Humans; Immunosuppressive Agents; Infant; Lymphatic Abnormalities; Macroglossia; Sirolimus

Topics: Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphatic Abnormalities; Male; Neck; Sclerotherapy; Sirolimus

Lymphatic anomalies (LAs) include several disorders in which abnormal lymphatic tissue invades the neck, chest, and various organs. Progressive cases may result in lethal outcomes and have proven difficult to treat. Sirolimus is showing promising results in the management of vascular anomalies. We examined the efficacy and safety of sirolimus treatment in patients with progressive LAs.. All patients with LAs treated with sirolimus from May 2015 to September 2018 were included. They received oral sirolimus once a day and the dose was adjusted so that the trough concentration remained within 5-15 ng/mL. We prospectively reviewed the response to drugs (the response rate of radiological volumetric change of the target lesion), severity scores, reported quality of life (QOL), and adverse effects at 6 months after administration.. Twenty patients (five with cystic lymphatic malformation (LM), three with kaposiform lymphangiomatosis, three with generalized lymphatic anomaly, six with Gorham-Stout disease, and three with central conducting lymphatic anomaly) were treated with sirolimus at our institution. Fifty percent of patients (10/20) demonstrated a partial response by a radiological examination and a significant improvement in disease severity and QOL scores (P = 0.0020 and P = 0.0117, respectively). Ten patients who had no reduction in lesion size (stable disease group) showed no significant improvement in disease severity and QOL scores. Eighty percent of patients (16/20) had side effects, such as stomatitis, infection, and hyperlipidemia.. Sirolimus impacts the reduction of the lymphatic tissue volume of LMs and could lead to improvement in clinical symptoms and QOL.. UMIN Clinical Trials Registry, UMIN000016580 . Registered 19 February 2015.

Topics: Administration, Oral; Adolescent; Adult; Child; Child, Preschool; Female; Humans; Infant; Lymphatic Abnormalities; Male; Middle Aged; Osteolysis, Essential; Prospective Studies; Quality of Life; Sirolimus; TOR Serine-Threonine Kinases; Vascular Malformations; Young Adult

Lymphatic malformations (LMs) are challenging to manage, particularly those involving the cervicofacial region and airway. Traditional therapy is sclerotherapy and/or resection. We aim to establish the emerging therapeutic role of sirolimus.. Institutional review board-approved retrospective review.. All patients treated for cervicofacial LM with sirolimus at Boston Children's Hospital, Massachusetts, from November 2012 to October 2016 were included. Chart review included response to therapy (defined as reduction in LM bulk by clinical photographs and radiologic imaging), type of LM (microcystic, macrocystic, mixed), extent of disease, duration of therapy, patient/parent-reported quality-of-life, airway status (tracheostomy dependence), and complications (opportunistic infection, hemorrhage, other). Follow-up and clinical outcomes were included up until October 2016.. Nineteen patients were treated with sirolimus for cervicofacial LM from November 2012 to October 2016 at Boston Children's Hospital. Seven patients remain on uninterrupted sirolimus. Of 12 patients who stopped therapy, seven have resumed due to recurrence of symptoms. All patients demonstrated reduction in LM bulk, ranging from modest to significant. All patients with mucosal vesicles (n = 14) resolved or improved on sirolimus. Six patients developed cellulitis, and four had bleeding within the LM during treatment. No patients developed opportunistic or systemic bacterial infection.. The use of sirolimus in the management of cervicofacial LM often is efficacious, with limited adverse events. Long-term follow-up, durability of response, and coordination of sirolimus prior to procedural therapies need further study.. 4. Laryngoscope, 128:269-276, 2018.

Topics: Child, Preschool; Face; Female; Humans; Immunosuppressive Agents; Infant; Lymphatic Abnormalities; Male; Neck; Quality of Life; Retrospective Studies; Sirolimus; Tracheostomy; Treatment Outcome

Generalized lymphatic anomaly is a rare, complex, lymphatic anomaly generally involving soft tissues, spleen, and bones. It can lead to focal skeletal fragility and pathologic effusions. A recent prospective trial of sirolimus for complicated vascular anomalies showed partial response in seven patients with generalized lymphatic anomaly treated with sirolimus with a target trough level of 10-15 ng/mL for 1 year (Adams et al). We describe successful treatment of generalized lymphatic anomaly with a lower-dose, long-term course of sirolimus.

Topics: Child, Preschool; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Magnetic Resonance Imaging; Male; Sirolimus

Efficacy of topical sirolimus has recently been described in lymphatic anomalies but not in other types of vascular anomalies. To our knowledge, systemic absorption of topical sirolimus in these lesions has not yet been reported. The objective was to evaluate the efficacy, tolerance, and absorption of topical sirolimus 0.1% with different types of vascular anomalies in children.. Sirolimus 0.1% was applied on cutaneous vascular anomalies in six children aged 2-17. These anomalies consisted of three extratruncular micro- and macrocystic lymphatic malformations and one each verrucous venous malformation, truncular lymphatic malformation with angiokeratomas, and infantile hemangioma. Sirolimus blood levels were measured after 1 week, 1 month, and 3 months.. A rapid decrease in the size of superficial lymphatic malformations in three of six patients and a significant decrease in discharge from oozing lesions were observed. Response occurred in less than 3 months. The truncular lymphatic malformation, verrucous venous malformation, and infantile hemangioma did not respond to topical sirolimus. Sirolimus levels were undetectable. Adverse effects were limited to local irritation.. Topical sirolimus 0.1% is a useful treatment for cutaneous manifestations of extratruncular lymphatic malformations. The only adverse effect is local irritation. No systemic effects are expected, because blood levels are clinically insignificant.

Topics: Adolescent; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Sirolimus; Treatment Outcome; Vascular Malformations

Microcystic lymphatic malformations (MLM) are low-flow vascular malformations composed of multiple small cysts. MLM usually affect deep-lying structures, which makes their treatment even more difficult and complex. A novel and interesting treatment is rapamycin, a mammalian target of rapamycin inhibitor that when orally administrated has offered favorable results. However, until recently, topical rapamycin had not been used in the treatment of MLM. Case 1 is a girl aged 13 years with extensive MLM affecting the muscles in the right buttock. The patient had received frequent cycles of cryotherapy, but they had failed to control the associated symptoms. In the previous 12 months, the patient had reported greater discomfort, swelling, exudate, and superinfection of the affected region. Because no specific treatment has yet been approved for MLM, and as a step before the use of aggressive systemic or intralesional treatments, it was decided to initiate treatment with 1% rapamycin ointment. After 4 months of treatment, the patient presented a marked improvement, with a significant reduction of associated complications and no major side effects. Case 2 is a boy aged 5 years who underwent surgery for an intergluteal lipoblastoma at 3 weeks of life and developed a MLM on the scar 6 months afterward. The lesion showed slow growth and continuous exudation with frequent episodes of superinfection. Treatments with laser multiplex and intralesional bleomycin were performed unsuccessfully. In the previous 4 months, the patient had been treated with 1% rapamycin ointment with significant improvement and no side effects.

Topics: Adolescent; Antibiotics, Antineoplastic; Child, Preschool; Female; Humans; Injections, Intralesional; Lymphatic Abnormalities; Male; Sirolimus; Vascular Malformations

Topics: Adolescent; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Sirolimus; Skin Diseases

Topics: Administration, Topical; Biopsy; Cysts; Genitalia, Male; Humans; Immunosuppressive Agents; Lymphatic Abnormalities; Male; Sirolimus; Treatment Outcome; Young Adult

To evaluate the effectiveness and safety of sirolimus therapy in a child with macroglossia due to lymphatic malformation.. Sirolimus treatment was applied to the patient with an initial dosing of 0.8 mg/m2 per dose, administered orally, twice daily at approximately 12-hour intervals.. After 9 months of sirolimus therapy, there was a nearly complete resolution of lymphatic malformation. The last evaluation was performed 6 months after withdrawal of treatment, and the lesion had almost completely resolved.. This article presents a novel approach to the treatment of lymphatic malformation of the tongue using sirolimus, which appears to be safe and effective for the management of complex cases.

Topics: Administration, Oral; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Female; Humans; Infant; Lymphatic Abnormalities; Macroglossia; Sirolimus; Treatment Outcome

Head and neck lymphatic malformations can create airway management challenges requiring tracheotomy. Sirolimus, an inhibitor of mammalian target of rapamycin (mTOR), may inhibit growth of lymphatic malformations. We describe two patients born with large lymphatic malformations with improved airway symptoms following sirolimus therapy. Patient #1 underwent tracheotomy and multi-modal therapy including sirolimus with reduction in airway involvement but regrowth after discontinuation of sirolimus. Patient #2 also experienced a significant response to sirolimus allowing for extubation and discharge without tracheotomy. Early initiation of sirolimus therapy should be considered as a means to avoid tracheotomy in complex head and neck lymphatic malformations.

Topics: Airway Obstruction; Combined Modality Therapy; Female; Head; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Lymphatic Abnormalities; Male; Neck; Recurrence; Sclerotherapy; Sirolimus; Tracheotomy

The therapy of vascular tumors and malformations should be interdisciplinary and performed according to available guidelines. Infantile hemangiomas (IH) are the most frequent vascular tumors of childhood and do not require treatment in most cases. If the IH is complicated by its location (e.g. facial or genital) or if the lesion threatens to cause loss of function, small localized IH should be treated by laser- or cryotherapy. If the IH is diffuse or rapidly growing it can be successfully treated using the β blocker propranolol. The mechanism underlying the efficacy of this medication-based therapy is not completely understood and this still represents an experimental therapy. The results of molecular studies on vascular malformations have indicated new strategies for medical therapies. However, lymphatic malformations (LM) are still treated by surgery where possible, or sclerotherapy. Further investigations are necessary to determine whether new drugs such as the mTOR inhibitor rapamycin may be effective for treatment of diffuse LM. First case reports seem to be promising.

Topics: Antibiotics, Antineoplastic; Female; Head and Neck Neoplasms; Hemangioma; Humans; Infant; Infant, Newborn; Lymphatic Abnormalities; Lymphatic Vessel Tumors; Male; Propranolol; Sirolimus; Vasodilator Agents