sirolimus and Hemangioendothelioma

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm of intermediate malignancy that generally occurs in infancy and early childhood. Typically, the lesion arises from superficial or deep soft tissues of the extremities, trunk and retroperitoneum. The paucity of reported cases of head and neck KHEs is evidence of the rarity of the disease in this region. We report on the presentation and treatment of KHE in an 11-month-old boy who presented with a mandibular lesion. We include a brief discussion about the differential diagnosis of KHE. Management involved preoperative interventional radiology, surgical excision and chemotherapeutic treatment with Sirolimus. The lesion resolved without evidence of relapse 12 months later.

Topics: Child, Preschool; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Sarcoma, Kaposi; Sirolimus

Hemangiondothelioma is a rare vascular tumor that can occur in the bone. Temporal bone involvement has been reported extremely rare in the literature.. Radiological examination of a one-year-old girl who was admitted due to facial paralysis revealed vascular tumor of the temporal bone and Galen vein aneurysm. Pathological examination showed retiform hemangioendothelioma. She was treated with propranolol, prednisolone, vincristine, and endovascular embolization followed by oral sirolimus. With sirolimus treatment, a partial response was obtained first, then the tumor remained stable and sirolimus treatment was discontinued. No progression was observed in the disease after discontinuation of treatment.. In this article, a case of hemangioendothelioma originating from the temporal bone is discussed in the light of other case reports in the literature.

Topics: Female; Hemangioendothelioma; Humans; Infant; Sirolimus; Temporal Bone; Vascular Neoplasms; Vincristine

Kaposiform haemangioendothelioma (KHE) is a rare, potentially life-threatening vascular tumour that is often associated with thrombocytopenia and coagulopathy, known as the Kasabach-Merritt phenomenon (KMP). Because of the rarity and complexity of KHE, the optimal paradigm for treating KHE has yet to be elucidated. We aim to assess the efficacy and safety of vincristine and sirolimus for the treatment of KHE.. A comprehensive review of the literature was conducted from January 1993 to June 2018. A total of 15 studies were selected for the meta-analysis. Five studies included 75 individuals and reported the response and side effects to vincristine in the treatment of KHE with or without KMP. A total of 10 studies that included 127 individuals reported the response and safety of sirolimus for treating KHE with or without KMP.. The pooled odds ratio (OR) for the effectiveness of vincristine was 0.72. The pooled OR for the effectiveness of sirolimus was 0.91. The side effects associated with vincristine during the treatment included neuropathy, abdominal pain, loss of appetite and mild elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The side effects associated with sirolimus therapy included bronchitis; lymphopenia; elevated AST, ALT and platelets; hyperlipidaemia; opportunistic infection; mild reversible leukopenia; mucositis; fever; pain and skin rash/vomiting and diarrhoea.. This systematic review showed a high efficacy of vincristine and sirolimus in the treatment of KHE. Based on the available data in the literature, it appears that sirolimus is potentially an efficacious and safe treatment option for KHE. Further randomised, controlled trials are recommended.

Topics: Female; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Male; Outcome Assessment, Health Care; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Vincristine

Vascular anomalies consist of a diverse group of disorders that are broadly categorized as tumors and malformations. . Recently, there has been significant genomic discovery allowing phenotype/genotype correlation of disease. An increasing number of pediatric hematologists/oncologists are caring for individuals with vascular anomalies as these patients require chronic care and have high medical acuity needs. The advent of new medical therapy options, along with ongoing and upcoming clinical trials, makes the involvement of hematologists/oncologists essential. This article highlights diagnosis and management of complicated vascular anomalies as well as important new treatment options and discoveries.

Topics: Antibiotics, Antineoplastic; Child; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Vascular Malformations

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor affecting infants and young children. Although benign, it can be associated with an aggressive locally growing tumor and/or a life-threatening Kasabach-Merritt phenomenon (KMP). To date, only reviews of limited cases have been performed. We, therefore, conducted a comprehensive literature search to collect relevant data and make recommendations for future treatment trials.. Review of the available literature between 1993 and 2017 revealed a total of 105 publications involving 215 patients of less than 21 years of age. To this, we added 12 from our department and 4 from the Cooperative Weichteilsarkomstudie database.. Patients with progressive KHE should undergo resection whenever it is considered a safe option. If inoperable, sirolimus should be the first choice for treating KMP and reducing tumor size.

Topics: Adolescent; Age of Onset; Cause of Death; Child; Child, Preschool; Cohort Studies; Combined Modality Therapy; Databases, Factual; Embolization, Therapeutic; Female; Germany; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Radiotherapy; Retrospective Studies; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Statistics, Nonparametric; Survival Analysis; Treatment Outcome; Vascular Neoplasms; Young Adult

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone vs sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100 × 109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% confidence interval, 10.0-44.7). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment of KHE with KMP. This trial was registered at www.clinicaltrials.gov as #NCT03188068.

Topics: Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Prednisolone; Sarcoma, Kaposi; Sirolimus

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0 months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P = .002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P = .047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.

Topics: Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus

Kaposiform haemangioendothelioma (KHE) is a rare, primarily paediatric tumour with only a handful of case reports in the adult population. Given the paucity of evidence, this article is important in raising awareness of radiotherapy as a suitable and effective treatment in the adult population with KHE and highlights the potential limitations of topical sirolimus in these tumours.

Topics: Administration, Topical; Aged; Antibiotics, Antineoplastic; Hemangioendothelioma; Humans; Immunosuppressive Agents; Kasabach-Merritt Syndrome; Magnetic Resonance Imaging; Male; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects.. A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m. In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen.. Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments.

Topics: Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

Topics: Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus

Topics: Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Neoplasms; Sarcoma, Kaposi; Sirolimus

Topics: Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus

Rapamycin has been recommended to treat Kaposiform hemangioendothelioma (KHE) with Kasabach-Merritt phenomenon (KMP), but the underlying mechanism of the clinical effect has not been established. Therefore, we determined rapamycin cytotoxicity on KHE cells in vitro and the underlying mechanism.. KHE primary cells were derived from a tumor specimen and treated with rapamycin. Immunofluorescence was applied to identify the cells. Cell viability was measured using the Cell Counting Kit-8 (CCK-8) assay. Cell cycle and apoptosis were assessed using flow cytometry (FCM). Western blots (WB) were performed to determine phosphorylation of mammalian target of rapamycin (mTOR), p70 S6 kinase (S6K1), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well light chain 3 (LC3) expression.. Rapamycin inhibited the growth of KHE primary cells in a dose- and time-dependent manner. Cell cycle progression was arrested in the G0/G1 phase and apoptosis was induced. WB results showed that LC3-II/I expression was significantly elevated in KHE primary cells treated with rapamycin, while the level of p-mTOR, p-S6K1, and p-4E-BP1 expression was reduced. LC3 fluorescent spots were increased in the rapamycin treatment group.. Rapamycin inhibited KHE primary cell proliferation, induced apoptosis and autophagy, and blocked the mTOR signaling pathway.

Topics: Apoptosis; Autophagy; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Phosphorylation; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases

This study aimed to in the management of Kasabach-Merritt phenomenon (KMP), a severe thrombocytopenic coagulopathy that occurs in the presence of an enlarging vascular tumor. Here, we retrospectively evaluated 12 patients with KMP in Guangzhou Women and Children's Medical Center, Guangzhou Medical University, from 2017 to 2021. 12 patients, including 7 females and 5 males, were identified. Tumors were located in the leg (n = 4), neck (n = 1), face (n = 3), chest wall (n = 1), back (n = 2), and retroperitoneum (n = 1). A plaque-like lesion with ecchymosis was the most common cutaneous manifestation. All the patients underwent embolization therapy. Nine patients received steroid treatment and 7 patients were administered with sirolimus. The mean duration of treatment was 1.6 months. All the patients reported in this study were alive when discharged. Embolization combined with steroid and sirolimus appears effective in patients with KMP, as well as in those who experienced disease recurrence. However, a long-term follow-up of the children cured of KMP will be necessary to monitor its recurrence and improve the outcome.

Topics: Child; Combined Modality Therapy; Female; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Neoplasm Recurrence, Local; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

Consumptive hypothyroidism may occur in hepatic hemangioendothelioma. The altered expression of deiodinases inactivates peripheral thyroid hormones. As a result, serum levels of free triiodothyronine and free thyroxine are reduced to varying degrees. There are no established recommendations for the dosage of sirolimus for this particular indication. We describe for the first time the course of treatment with low-dose sirolimus.. We present a 5-week-old infant with hepatic hemangioendothelioma and severe consumptive hypothyroidism. Due to hepatic infiltration he showed signs of right heart strain. Therapy of hemangioendothelioma was initiated with propranolol and, in the absence of response, methylprednisolone was added. Treatment was continued with low-dose sirolimus (due to side effects) and propranolol. Hypothyroidism was managed with levothyroxine and liothyronine.. Consumptive hypothyroidism due to cutaneous hemangioma and hepatic hemangioendothelioma can be managed with propranolol and low-dose sirolimus. Treatment of severe hypothyroidism may require a combinational therapy by substitution of both T3 and T4.

Topics: Hemangioendothelioma; Humans; Hypothyroidism; Infant; Liver Neoplasms; Male; Propranolol; Sirolimus; Thyroid Hormones; Thyroxine; Triiodothyronine

Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare disease that affects mainly the young and more men than women. PHE are multicentric, locally aggressive, have low metastatic potential, and affect multiple tissue planes. Genetic aberrations are frequently detected in PHE and may play important roles in the occurrence, development, and treatment of this disease. In this study, we report a case of PHE with a novel SERPINE1-FOSB fusion gene. The fusion introduced a strong promoter near the coding region of FOSB, resulting in overexpression of intact FOSB. Immunohistochemical analysis showed overexpression of pAKT and mTOR in tumor cells, suggesting activation of the PI3K-AKT-mTOR signaling pathway. The patient responded well to targeted therapy with sirolimus, an mTOR inhibitor. Our study correlated dysregulation of a specific signaling pathway and the effectiveness of a targeted therapy to a specific genetic aberration. This information may be useful for future investigations of targeted therapeutics and provide a potential predictive biomarker for therapeutic effectiveness in PHE cases.

Topics: Female; Hemangioendothelioma; Humans; Male; Phosphatidylinositol 3-Kinases; Plasminogen Activator Inhibitor 1; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-fos; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Antibiotics, Antineoplastic; Biopsy; Child, Preschool; Female; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Sarcoma, Kaposi; Sirolimus; Skin Cream; Treatment Outcome

Topics: Embolization, Therapeutic; Female; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Male; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

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

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor that occurs in children. Prox1 is a specific lymphatic marker for KHE. We intended to establish a Prox1 transgenic cell line resembling KHE and investigate the mechanism of sirolimus in treating KHE.. Prox1 was stably expressed in infantile hemangioma cell HemECs. RT-qPCR and Western blot were conducted to measure the expression of target genes. CCK-8, EdU assay, and cell cycle analysis were conducted to detect cell proliferation. Wound healing and transwell assay were used to evaluate cell migration and invasion.. Stable overexpression of Prox1 in HemECs induced a lymphatic endothelial reprogramming, and enhanced aggressive biological effects, partly resembled the invasion of KHE, and could serve as a novel model for KHE. Sirolimus may block mTOR-mediated pathways and induced autophagy in KHE.

Topics: Child; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus

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

Kaposiform hemangioendothelioma is an aggressive vascular tumor with infiltrative growth that commonly occurs in infancy and is associated with a life-threatening consumptive coagulopathy, as well as Kasabach-Merritt phenomenon. Recently, promising results have shown that sirolimus had been successfully used to treat Kasabach-Merritt phenomenon without significant toxicity. However, the situation the authors encountered in treating infants was not so satisfactory. Here, the authors present 2 patients younger than 3 months with refractory Kaposiform hemangioendothelioma treated with sirolimus and experienced severe pneumonia. The outcomes suggest that it is necessary to keep an eye on any symptoms indicate the infection of respiratory tract and use the antibiotics in time. The 2 cases also remind us of the potential sign that indicate the recurrence of KMP, which refers to firmer lesion with deepen color, especially when it comes with complications.

Topics: Blood Coagulation Disorders; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Sarcoma, Kaposi; Sirolimus; Vascular Neoplasms

We present a retrospective case series of 3 patients with retroperitoneal kaposiform hemangioendothelioma (KHE) complicated by Kasabach-Merritt phenomenon (KMP) and biliary obstruction. We found sirolimus to be a safe and effective treatment for these patients who were refractory to other treatment modalities. However, our patients were slow to respond in comparison to published reports of sirolimus use for KHE without biliary obstruction. We postulate that therapeutic serum levels of sirolimus may be affected by biliary obstruction and improved with surgical alleviation of the obstruction.

Topics: Hemangioendothelioma; Humans; Jaundice, Obstructive; Kasabach-Merritt Syndrome; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that may be associated with Kasabach-Merritt Phenomenon (KMP), which is a consumptive coagulopathy with potentially life-threatening thrombocytopenia. Management of KHE and KMP is challenging, and currently, there are no standardized validated treatment protocols. Mammalian target of rapamycin inhibitors have been shown to be effective in the treatment of KHE. We describe a term male who presented as a diagnostic dilemma with life-threatening pleural and pericardial effusions and severe thrombocytopenia. After extensive work-up the etiology for his condition was determined to be KHE with KMP. The patient was commenced on sirolimus and responded well to therapy with resolution of KMP.

Topics: Hemangioendothelioma; Humans; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Pericardial Effusion; Pleural Effusion, Malignant; Sarcoma, Kaposi; Sirolimus

Mammalian target of rapamycin inhibitors have shown promising results in the management of kaposiform hemangioendothelioma (KHE). The purpose of this study was to present our experience involving sirolimus therapy for KHE. A retrospective study was conducted to review the medical documents of 26 patients with KHE who were treated with sirolimus at our hospital between March 2012 and December 2016. Fifteen males and 11 females manifested KHE in infancy with an average age of 2.9 ± 1.8 months. Multiple anatomical sites were involved. Four patients had multifocal lesions, while 22 patients had solitary lesions. Twenty-five patients had Kasabach-Merritt phenomenon (KMP). Twenty patients completed sirolimus therapy in 28.3 ± 12.5 months. Nineteen KHE lesions reduced to small residuals with platelet counts reaching normal levels 3.7 ± 2.8 weeks after treatment; one KHE lesion had no response to therapy. One patient with multifocal lesions died due to a severe infection, although the patient had previously responded to sirolimus. Five patients remained in treatment and had good responses with normal platelet counts. Nineteen patients with anemia had normal hemoglobin levels after 3.5 ± 1.9 weeks of treatment. Mild side effects were observed. The median follow-up time was 32 months (26-60 months), with no evidence of recurrences. Sirolimus was shown to be efficacious in the management of KHE with an average course of 28 months. The time-to-response was variable, with an average of 1 week. After 4 weeks of treatment, the platelet count and hemoglobin level had normalized. Multifocal KHE with KMP is more severe than solitary KHE.

Topics: Antibiotics, Antineoplastic; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

Topics: Adult; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Immunocompromised Host; Kasabach-Merritt Syndrome; Male; Middle Aged; Pneumocystis carinii; Pneumonia, Pneumocystis; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Vincristine

Topics: Adolescent; Antibiotics, Antineoplastic; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Hemangioendothelioma; Hemangioma; Humans; Kasabach-Merritt Syndrome; Male; Prognosis; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Pseudomyogenic hemangioendothelioma (PMH) is a rare neoplasm with vascular and sarcomatous elements, unpredictable course, and uncommon metastatic or fatal potential. Although systemic chemotherapy has been reported with variable success, generally accepted treatment is aggressive surgery with wide margins. Evidence-based treatment options are lacking, and lack of clear prognostic features poses a risk of undertreatment or overtreatment with associated morbidity and mortality. We report the use of initial systemic therapy with oral sirolimus (SIR) and IV zoledronic acid (ZA) to induce a sustained clinical response and avoidance of amputation in a 6-year-old boy. At 37 months after diagnosis, our patient remains in sustained clinical remission as documented by x-ray, MRI, and PET-CT with return of normal mobility/activity and resolution of swelling and pain. Literature review identified 20 cases of pediatric and young adult patients with PMH, of which 7 received some form of systemic therapy. To the best of our knowledge, our patient represents the youngest reported case of PMH and the first successful and limb-sparing utilization of systemic chemotherapy as primary treatment for PMH.

Topics: Bone Neoplasms; Child; Hemangioendothelioma; Humans; Male; Multimodal Imaging; Sirolimus; Zoledronic Acid

Topics: Antineoplastic Agents; Child; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Lymphangioma, Cystic; Male; Mesentery; Peritoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Pseudomyogenic hemangioendothelioma (PMH) is a rare, mostly indolent vascular tumor. Extensive cases are treated with amputation as chemotherapy seems to be ineffective. Recently, promising results were published using mammalian target of rapamycin (mTOR) inhibitors in tumors of vascular origin. Here, we present a case of a child with advanced PMH relapsing after surgery and chemotherapy. Sirolimus achieved significant clinical improvement and stabilization of the lesions without any remarkable toxicity. This case contributes to the growing evidence regarding the efficacy of mTOR inhibitors, such as sirolimus, in multifocal PMH.

Topics: Child; Hemangioendothelioma; Humans; Male; Sirolimus; TOR Serine-Threonine Kinases; Vascular Neoplasms

Kaposiform hemangioendothelioma (KHE) is a rare vascular tumor characterized by aggressive local invasion and a syndrome of platelet trapping known as Kasabach-Merritt phenomenon that, through deposition of platelet derived growth factors, may perpetuate the growth of the tumor. Although many cases of KHE are successfully treated with local control or low-intensity chemotherapy, some cases are often refractory even to aggressive treatment. Herein, we describe a patient with a refractory, recurrent KHE despite multiple attempts at local control and intensive chemotherapy, that ultimately was successfully treated with rationally designed and low-intensity combination therapy of sirolimus and aspirin.

Topics: Aspirin; Child; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Male; Sarcoma, Kaposi; Sirolimus

Topics: Antineoplastic Agents; Drug Administration Schedule; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Treatment Outcome; Vascular Neoplasms

Sirolimus is an effective therapy for children with kaposiform hemangioendothelioma with or without the Kasabach-Merritt phenomenon. We report the case of a child with kaposiform hemangioendothelioma and the Kasabach-Merritt phenomenon who developed

Topics: Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Drug Therapy, Combination; Hemangioendothelioma; Humans; Immunosuppressive Agents; Infant; Kasabach-Merritt Syndrome; Male; Pneumocystis carinii; Pneumonia, Pneumocystis; Prednisolone; Propranolol; Respiratory Insufficiency; Sarcoma, Kaposi; Sirolimus; Vincristine

Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that is potentially life-threatening when presenting with Kasabach-Merritt phenomenon (KMP). KMP is clinically characterized as severe thrombocytopenia and hypofibrinogenemia and therefore is associated with a high mortality rate. There is no standard of cure for KHE currently. Potential medications, including corticosteroids, propranolol, and chemotherapy drugs such as sirolimus, are often used for alleviating KHE symptoms. Although some case reports of sirolimus treatment have shown promising results with recovered coagulant parameters, the off-target effects may cause severe problems. Here we describe 2 cases of infant patients with KHE and KMP who were scheduled to receive sirolimus on a long-term basis. However, both patients developed paroxysmal cough and tachypnea shortly after the onset of sirolimus treatment and succumbed to infection thereafter. This report reveals a potential risk of infection in sirolimus-treated infant patients. The fatal complication highlights the importance of antibiotic prophylaxis and serum sirolimus level monitoring to ensure the safe use of sirolimus in the treatment of infant patients with KHE.

Topics: Antibiotics, Antineoplastic; Bronchopneumonia; Fatal Outcome; Female; Hemangioendothelioma; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Mycoplasma pulmonis; Pneumonia, Mycoplasma; Sarcoma, Kaposi; Sirolimus

Kaposiform hemangioendothelioma (KHE) is a rare and aggressive vascular tumor that can be associated with a consumptive coagulopathy and thrombocytopenia (Kasabach-Merritt phenomenon). Only one case of an intracardiac KHE has been reported which was treated with surgical excision and then expectant management.. We present a patient with an intracardiac KHE which presented as a large mass surrounding the atria, pulmonary veins, superior vena cava, and infiltrating the atrial septum with moderate compression of the superior vena cava and mild compression of the pulmonary veins. This tumor clinically presented as persistent tachypnea and was unresponsive to conventional therapy with vincristine and steroids but responded dramatically to Sirolimus with almost complete regression on follow-up.. None of the current treatments for KHE, alone or in combination therapy have been found to be effective in a uniform or reproducible manner. Well designed, preferably randomized trials are required for a better understanding of the appropriate dosage and duration as well as response to treatment and a consensus of first and second line therapies.

Topics: Heart Diseases; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Pulmonary Veins; Salvage Therapy; Sarcoma, Kaposi; Sirolimus; Steroids; Tachypnea; Vincristine

A full-term newborn with kaposiform hemangioendothelioma (KHE) affecting the right thigh with thrombocytopenia due to Kasabach-Merritt phenomenon (KMP) was referred to our center. After biopsy, he rapidly evolved to severe thrombocytopenia and severe coagulopathy. Standard therapy was initiated with prednisolone and vincristine. His coagulopathy worsened to life-threatening hemorrhage necessitating aggressive blood products replacement. Sirolimus was added; he became transfusion independent with no further bleeding and reduction in tumor size. Addition of sirolimus to treatment of vascular anomalies with hemostatic complications should be considered as part of early treatment for patients with KMP/KHE.

Topics: Antineoplastic Combined Chemotherapy Protocols; Blood Coagulation Disorders; Child; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Male; Prednisolone; Sarcoma, Kaposi; Sirolimus; Thrombocytopenia; Vincristine

Kasabach-Merritt phenomenon (KMP) occurred uniquely in patients with kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). We report the clinical characteristics of two patients with KHE involving the right upper arm. The patients demonstrated rapid enlargement of the lesion with severe KMP shortly after vaccination. Sirolimus was used to treat the KHE with KMP. The patients showed a quick normalization of the platelet level. The follow-up examination revealed that the size of the mass was significantly decreased. This report raises the intriguing possibility that extrinsic factors may contribute to the development of KMP in the context of an already existing KHE.

Topics: Antibiotics, Antineoplastic; BCG Vaccine; Diphtheria-Tetanus-acellular Pertussis Vaccines; Female; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Magnetic Resonance Imaging; Male; Sarcoma, Kaposi; Sirolimus; Treatment Outcome; Vaccination

Topics: Administration, Oral; Antibiotics, Antineoplastic; Child, Preschool; Drug Administration Schedule; Female; Hemangioendothelioma; Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Male; Neoplasms, Vascular Tissue; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

Kaposiform hemangioendothelioma (KHE) is an aggressive disease with high morbidity and mortality. The aim of this study was to retrospectively evaluate the efficacy and safety of sirolimus for the treatment of progressive KHE. A multicenter, retrospective cohort study was conducted in patients with progressive KHE treated with sirolimus. A total of 52 patients were analyzed. Thirty-seven (71%) patients exhibited Kasabach-Merritt phenomenon (KMP) and were significantly younger than the patients without KMP [95% confidence interval (CI), 14.39-41.61; p < 0.001]. Patients without KMP were all treated with sirolimus alone, whereas 21 KMP patients with severe symptoms received short-term combination therapy with prednisolone. Overall, 96% and 98% of patients showed improved relief of notable symptoms and/or improved complications at 6 and 12 months after treatment, respectively. After sirolimus treatment, significant decreases in mean severity scores occurred at 6 months (95% CI, 2.23-2.54, p < 0.001) and 12 months (95% CI, 1.53-1.90, p < 0.001). Compared to KMP patients, patients without KMP showed a response that was similar to but less pronounced during the 12 months of treatment (95% CI, 40.87-53.80; p < 0.001). For subgroup analysis of KMP patients, there were no significant differences in tumor shrinkage between those treated with combination therapy and those receiving sirolimus alone (95% CI, 18.11-25.02; p > 0.05). No patients permanently discontinued treatment due to toxicity-related events, and no drug-related deaths occurred. Sirolimus was effective and safe for the treatment of progressive KHE. Sirolimus may be considered as a first-line therapy or as part of a multidisciplinary approach for the treatment of KHE.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Child; Child, Preschool; Female; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Middle Aged; Prednisolone; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Treatment Outcome; Young Adult

Topics: Antibiotics, Antineoplastic; Female; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Topics: Hemangioendothelioma; Humans; Immunosuppressive Agents; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus

Topics: Female; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Platelet Count; Sarcoma, Kaposi; Sirolimus

There is currently no consensus on the second-line management of Kaposiform hemangioendothelioma (KHE) that was resistant to prednisolone and vincristine. We described an eight-year-old male with KHE in the right femur that was resistant to prednisolone, vincristine and propranolol. Everolimus, an inhibitor of mammalian target of rapamycin (mTOR) at the dosage of 0.1 mg/kg/day, successfully decreased the tumor size and controlled the symptoms. Everolimus should be further studied as an alternative agent to sirolimus in the management of KHE.

Topics: Antineoplastic Combined Chemotherapy Protocols; Child; Drug Resistance, Neoplasm; Everolimus; Hemangioendothelioma; Humans; Immunosuppressive Agents; Kasabach-Merritt Syndrome; Male; Prednisolone; Propranolol; Sarcoma, Kaposi; Sirolimus; Vincristine

Generalized lymphatic anomaly (GLA) is a rare and often fatal congenital lymphatic disorder that also commonly affects bone. Kaposiform lymphangiomatosis (KLA) is a novel subtype of GLA with poor prognosis and no proper treatment guidelines. A 9-year-old male with recurrent pleural effusion was clinically diagnosed as KLA. Following sirolimus therapy at a dose of 0.8 mg/m(2) twice daily, pleural effusion was significantly decreased and the general status of the patient markedly improved. The clinical course indicates that sirolimus may present an effective therapeutic option in KLA. Moreover, KLA should be considered in differential diagnosis for cases of GLA with coagulopathy.

Topics: Antibiotics, Antineoplastic; Child; Hemangioendothelioma; Humans; Kasabach-Merritt Syndrome; Male; Pleural Effusion; Prognosis; Sarcoma, Kaposi; Sirolimus

Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor that usually occurs in infants. It is commonly associated with Kasabach-Merritt phenomenon which is directly responsible for the significant morbidity and mortality, including hemodynamic instability, local invasion, and compression of vital structures. Treatment is particularly difficult for those who had no response to conventional therapies. This paper wants to share experience of mTOR inhibitors sirolimus in the treatment of refractory KHE.. Six cases of refractory KHE were diagnosed and treated in Children's Hospital of Fudan University from Jan 2010-June 2013; all of them were treated with sirolimus in June 2012 after failing multiple other therapies.. In six patients, gender was equally distributed between male and female patients. The mean age at the time of initial diagnosed as KHE was 3.1 ± 1.8 months. All of them had been pretreated with at least 2 medical therapies. All of them showed significant improvement in clinical status with tolerable side effects. The average time to response was 5.3 ± 1.0 days; the average stabilization time of platelet was 15.1 ± 8.0 days; and the average time for sirolimus treated as single agent was 1.7 ± 0.4 months. No recurrence of their symptoms happened.. Sirolimus appears to be effective and safe in patients with life-threatening KHE and represents a promising tool in treating refractory KHE.

Topics: Antibiotics, Antineoplastic; Drug Administration Schedule; Female; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Male; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.

Topics: Combined Modality Therapy; Glottis; Hemangioendothelioma; Humans; Infant; Kasabach-Merritt Syndrome; Laryngomalacia; Laryngoplasty; Laser Therapy; Male; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases

Topics: Contusions; Diagnosis, Differential; Female; Hemangioendothelioma; Humans; Immunosuppressive Agents; Infant; Kasabach-Merritt Syndrome; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Topics: Antibiotics, Antineoplastic; Enchondromatosis; Hemangioendothelioma; Humans; Male; Sirolimus; Young Adult

Topics: Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Platelet Count; Prednisolone; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Vincristine

Sirolimus (Rapamune), a mammalian target of Rapamycin (mTOR) inhibitor, which has been used extensively in children following solid organ transplantation, has been demonstrated to have anti-angiogenic activity in pre-clinical models. Limited experience suggests that it may have application to the treatment of vascular lesions. We describe our experience with a 1-year-old female with a kaposiform hemangioendothelioma and Kasabach-Merritt phenomenon who had rapid and dramatic response to sirolimus (0.1 mg/kg/day). This case provides further rationale for clinical trials of sirolimus in the treatment of vascular lesions.

Topics: Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Female; Hemangioendothelioma; Humans; Infant; Platelet Count; Sirolimus; Skin Neoplasms