sirolimus and Sarcoma--Kaposi

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

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

Over the past two decades, advances in the fields of cancer genetics and molecular biology have elucidated molecular pathways that cause numerous cutaneous malignancies. This in turn has spurred the rational design of molecularly targeted therapies. In this review, we discuss the molecular pathways critical to the development of nonmelanoma skin cancers and the novel pharmacologic agents that target them. Included is a review of vismodegib for basal cell carcinoma, cetuximab for squamous cell carcinomas, imatinib for dermatofibrosarcoma protuberans, and sirolimus for Kaposi's sarcoma.

Topics: Anilides; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Benzamides; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cetuximab; Dermatofibrosarcoma; Humans; Imatinib Mesylate; Piperazines; Pyridines; Pyrimidines; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Skin cancer is the most frequent malignancy in organ transplant recipients, 95% of which are nonmelanoma skin cancer, especially squamous cell and basal cell carcinomas. This paper also discusses the incidence of other tumors (eg, melanoma, Merkel cell carcinoma, and Kaposi sarcoma) that are also increased in organ transplant patients compared to the general population. Part I of this two-part series describes the latest data concerning the epidemiologic and pathogenic aspects of nonmelanoma skin cancer development in solid organ transplant recipients. This review also highlights the concept of "field cancerization," represented by extensive areas of actinic damage and epidermal dysplasia, which accounts for increased risk of aggressive skin cancer development in susceptible patients.

Topics: Carcinoma, Basal Cell; Carcinoma, Merkel Cell; Carcinoma, Squamous Cell; Education, Medical, Continuing; Female; Humans; Immunocompromised Host; Incidence; Male; Melanoma; Organ Transplantation; Prognosis; Pyrimidines; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Survival Analysis; Treatment Outcome; Triazoles; Voriconazole

Topics: Calcineurin Inhibitors; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Patient Selection; Protein Kinases; Risk Factors; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases; Transplantation Immunology; Treatment Outcome

Kaposi sarcoma (KS) is a multicentric neoplasm of lymphatic endothelium derived cells infected with Kaposi's human herpesvirus 8 (HHV8). Post-transplant KS can lead to multifocal, progressive (florid) lesions with frequent primary involvement of the oral mucosa and dissemination to the viscera. KS prevalence after organ transplantation varies greatly depending on the prevalence of HHV8 infection in the general population. Most cases of post-transplant KS develop as a result of viral reactivation. Immunohistochemistry using a monoclonal antibody against HHV8 latent nuclear antigen on paraffin embedded sections, although less sensitive than polymerase chain reaction, is useful for pathological diagnosis of difficult angiogenic proliferations. Although HHV8 viral load in peripheral blood mononuclear cells of KS individuals correlates with tumor burden, due to low interval variations this test cannot be used in clinical practice to monitor KS patients nor to predict the occurrence of KS in transplant recipients. The main objectives of KS treatment is to control disease progression and relieve symptoms, as opposed to achieving complete tumor remission. The cornerstone in treatment of post-transplant KS is to taper down immunosuppressive regimens to the lowest possible level, while attempting to keep the allograft functional. Specific local or, less frequently, systemic treatment modalities can be used such as chemotheraphy. Other therapeutic strategies could rely in targeting signaling pathways important for HHV8 de novo infection, reaction, cell persistence or cellular pathways activated by viral pirated genes such as the mitogen-activated protein kinase or the PI3 kinase pathway. Rapamycin, a mammalian target of rapamycin inhibitor located downstream the PI3 kinase, has already proven of benefit and should be discussed in all post-transplant KS.

Topics: Enzyme-Linked Immunosorbent Assay; Graft Survival; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Neoplasm Staging; Polymerase Chain Reaction; Sarcoma, Kaposi; Sirolimus; Transplants

The incidence of Kaposi's sarcoma (KS) among the recipients of solid organ transplants is about 500 times the rate in the general population, suggesting a role for immunosuppression in the development of the disease. The drugs used for the induction and maintenance of immunosuppression and the length of treatment with these agents influence both the incidence and the type of cancer development. The clinical presentation of KS in transplant recipients is often limited to the skin. The risk of death from KS is related to the form and extent of the lesions. The main approach to managing transplant-associated KS is to reduce or even discontinue immunosuppressive therapy; this strategy carries a risk of acute rejection of the graft. KS is a multicentric tumor composed of endothelium-lined vascular spaces and spindle-shaped cells. Its pathogenesis is unclear. Recent evidence suggests that vascular endothelial growth factor (VEGF) is likely to be a growth factor for KS cells: blocking the interaction between VEGF and Flk-1/KDR can abolish VEGF-induced growth of the tumor. Recently, Sirolimus, a drug used in kidney-transplant recipients, has been suggested to reduce KS progression in transplant recipients. This unexpected effect of the drug confirms previous experimental information on KS pathogenesis and may shed light on an array of molecular mechanisms, modulated by Sirolimus, of potential clinical interest in the transplantation scenario.

Topics: Herpesvirus 8, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Neovascularization, Pathologic; Organ Transplantation; Protein Kinases; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Kaposi's sarcoma (KS) is an enigmatic vascular neoplasm that has reached epidemic proportions in parts of the developing world and is a leading cause of morbidity and mortality among the AIDS population. Unfortunately, KS is still difficult to manage therapeutically, especially in its most advanced clinical manifestations. The recent identification of the KS-associated herpesvirus (KSHV or HHV8) as its viral etiologic agent has prompted renewed interest in the molecular pathogenesis of this disease. Emerging evidence now points to a single KSHV gene, vGPCR, as essential for KS development, providing a unique opportunity to expose new targets for the treatment of this tumor. In this regard, recent work has identified the Akt/TSC/mTOR signaling cascade as a critical pathway in vGPCR sarcomagenesis. Indeed, pharmacological inhibition of mTOR with rapamycin has shown promising results in preventing vGPCR tumorigenesis in an animal model for KS. These observations are further validated by coincident reports demonstrating the efficacy of rapamycin (sirolimus) as an immunossuppresive and anti-tumoral solution for posttransplant KS patients. Collectively, these data suggest that inhibition of the Akt/TSC/mTOR signaling pathway may provide a novel molecular-based approach for the treatment of patients who currently have a paucity of therapeutic options.

Topics: Animals; Antibiotics, Antineoplastic; Calcium-Binding Proteins; Herpesvirus 8, Human; Humans; Mice; Models, Biological; Protein Kinases; Proto-Oncogene Proteins c-akt; Receptors, Chemokine; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Viral Proteins

The incidence of Kaposi's sarcoma (KS) is greatly increased in renal transplant recipients compared with the general population, with particular prevalence in certain ethnic groups where it can occur in up to 5% of transplant recipients. The increased incidence of disease in transplant populations may, in part, be attributed to the choice of immunosuppressive regimen, with calcineurin inhibitor (CNI)-based immunosuppression being associated with the development of the tumour. A number of small studies have recently demonstrated that conversion to proliferation signal inhibitors (PSIs) along with the concomitant withdrawal of CNIs leads to a rapid resolution of both cutaneous and visceral Kaposi's lesions. In agreement with these data the abrupt onset of KS has been observed following the withdrawal of PSIs. Histological examination of lesions from patients with KS supports data from animal models which suggests that PSIs inhibit tumour angiogenesis through impaired vascular endothelium growth factor production, a key element in the development of the tumour. Previously unpublished data on renal transplant recipients from a number of European and Australian centres have been pooled to provide further insight into the use of PSIs in the management of post-transplant KS. Both members of the PSI class, everolimus and sirolimus, along with CNI withdrawal lead to regression of KS lesions in 11 out of 12 patients. Conversion to PSIs was generally well tolerated with stable renal function maintained in most patients and no episodes of acute rejection recorded. PSIs provide a potential treatment option in the management of post-transplant KS and should be considered for use in renal transplant recipients who develop the disease.

Topics: Calcineurin Inhibitors; Everolimus; Humans; Immunosuppressive Agents; Kidney Transplantation; Protein Kinases; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Discovered in fungi in the remote Easter Island, sirolimus (rapamycin) shows potential beyond its obvious antiproliferative and immunosuppressant activity. Studies have demonstrated that sirolimus acts as a vascular endothelial growth factor inhibitor, providing prospective therapeutic benefits and possible prevention of tuberous sclerosis and Kaposi's sarcoma. Its ability to decrease keratinocyte proliferation may help patients with psoriasis. In those with tuberous sclerosis complex, it may prevent the development of hamartomas and reduce or eliminate them once grown by blocking the mammalian target of rapamycin, a critical regulatory kinase. A great advantage for this drug is in the decreased risk of malignancies, including Kaposi's sarcoma, associated with its use compared with other immunosuppressants, namely calcineurin inhibitors. This review will focus on the pharmacology and potential uses of sirolimus.

Topics: Animals; Humans; Immunosuppressive Agents; Psoriasis; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Topics: Acute Disease; Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Kidney Transplantation; Leukemia; Neoplasms; Postoperative Complications; Sarcoma, Kaposi; Sirolimus

Topics: Adult; Aged; Angiogenesis Inhibitors; Donor Selection; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Incidence; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Organ Transplantation; Randomized Controlled Trials as Topic; Reoperation; Risk Factors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tissue Donors; TOR Serine-Threonine Kinases; Tumor Escape

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

The clinical challenge for the application of rapamycin and its derivatives as anticancer drugs is the ability to prospectively identify which tumors will be sensitive to mammalian target of rapamycin (mTOR) inhibition. The present study is designed to explore mTOR signaling in peripheral-blood mononuclear cells (PBMCs) from renal transplant recipients with Kaposi sarcoma and ascertain whether it would reflect deregulation of the AKT-mTOR pathway in skin cancer tissue and might help identify which patients would benefit from rapamycin treatment, as well as to monitor their clinical response.. We measured basal and in vivo stimulated AKT and P70 S6 kinase (P70(S6K)) phosphorylation in PBMCs from 37 cyclosporine A-treated patients, 10 of whom had Kaposi sarcoma, before and 6 months after conversion to rapamycin therapy.. Patients with Kaposi sarcoma showed markedly increased basal P70(S6K) activation and depressed phosphorylation of AKT. Long-term treatment with rapamycin was associated with marked inhibition of basal and stimulated phosphorylation of both AKT and P70(S6K), in parallel with regression of the dermal neoplasm.. Overactivation of basal P70(S6K) in PBMCs from renal transplant recipients appears to be associated with the presence of Kaposi sarcoma dermal lesions; conversely, kinase inhibition is linked to regression of skin cancer lesions. Thus, monitoring P70(S6K) phosphorylation can help predict and monitor the biological effectiveness of rapamycin in renal transplant recipients with Kaposi sarcoma and possibly adjust the biologically active doses of the mTOR inhibitor.

Topics: Adult; Antineoplastic Agents; Biomarkers; Female; Humans; Kidney Transplantation; Male; Middle Aged; Monocytes; Patient Selection; Phosphorylation; Predictive Value of Tests; Protein Kinases; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sarcoma, Kaposi; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Recipients of organ transplants are susceptible to Kaposi's sarcoma as a result of treatment with immunosuppressive drugs. Sirolimus (rapamycin), an immunosuppressive drug, may also have antitumor effects.. We stopped cyclosporine therapy in 15 kidney-transplant recipients who had biopsy-proven Kaposi's sarcoma and began sirolimus therapy. All patients underwent an excisional biopsy of the lesion and one biopsy of normal skin at the time of diagnosis. A second biopsy was performed at the site of a previous Kaposi's sarcoma lesion six months after sirolimus therapy was begun. We examined biopsy specimens for vascular endothelial growth factor (VEGF), Flk-1/KDR protein, and phosphorylated Akt and p70S6 kinase, two enzymes in the signaling pathway targeted by sirolimus.. Three months after sirolimus therapy was begun, all cutaneous Kaposi's sarcoma lesions had disappeared in all patients. Remission was confirmed histologically in all patients six months after sirolimus therapy was begun. There were no acute episodes of rejection or changes in kidney-graft function. Levels of Flk-1/KDR and phosphorylated Akt and p70S6 kinase were increased in Kaposi's sarcoma cells. The expression of VEGF was increased in Kaposi's sarcoma cells and even more so in normal skin cells around the Kaposi's sarcoma lesions.. Sirolimus inhibits the progression of dermal Kaposi's sarcoma in kidney-transplant recipients while providing effective immunosuppression.

Topics: Antibiotics, Antineoplastic; Biopsy; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sarcoma, Kaposi; Signal Transduction; Sirolimus; Skin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

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

Calcineurin inhibitors (CNIs), including cyclosporine and tacrolimus, are associated with an increased cancer risk. However, whether mammalian target of rapamycin inhibitors (mTORis), including sirolimus and everolimus, decrease the cancer risk in patients receiving CNIs remains uncertain. We aimed to determine whether mTORis are associated with a decreased cancer risk in patients receiving CNIs using data mining of a spontaneous adverse reaction database.. Disproportionality analysis was conducted using the U.S. Food and Drug Administration Adverse Event Reporting System database (2004 - 2019) with reporting odds ratio and information component being used to indicate a signal.. Data subset analyses indicated that sirolimus and everolimus were not associated with a decreased cancer risk in patients receiving cyclosporine or tacrolimus but were associated with an increased risk of nonmelanoma skin cancer (NMSC) and Kaposi's sarcoma.. mTORis are not associated with a decreased cancer risk but are associated with a further increase in the risk of NMSC and Kaposi's sarcoma in patients receiving CNIs. Further studies are necessary to clarify the mechanism underlying the association between mTORis and NMSC or Kaposi's sarcoma.

Topics: Calcineurin Inhibitors; Cyclosporine; Data Mining; Everolimus; Humans; Immunosuppressive Agents; Sarcoma, Kaposi; Sirolimus; Tacrolimus; 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

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

Systemic therapeutic management of post-transplant Kaposi sarcoma (KS) is mainly based on 3 axes: reduction of immunosuppression, conversion to mammalian target of rapamycin (mTOR) inhibitors, chemotherapy, or a combination of these.. To obtain an overview of clinical strategies about the current treatment of KS.. We conducted a multicenter retrospective cohort study including 145 solid organ transplant recipients diagnosed with KS between 1985 and 2011 to collect data regarding first-line treatment and response at 6 months.. Overall, 95%, 28%, and 16% of patients had reduction of immunosuppression, conversion to mTOR inhibitor, and chemotherapy, respectively. Patients treated with chemotherapy or mTOR inhibitor conversion were more likely to have visceral KS. At 6 months, 83% of patients had response, including 40% complete responses.. The retrospective design of the study.. Currently available therapeutic options seem to be effective to control KS in most patients. Tapering down the immunosuppressive regimen remains the cornerstone of KS management.

Topics: Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Substitution; Europe; Female; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Organ Transplantation; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Survival Rate; Tacrolimus; TOR Serine-Threonine Kinases

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

Mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cellular metabolism. In nutrient-rich environments, mTORC1 kinase activity stimulates protein synthesis to meet cellular anabolic demands. Under nutrient-poor conditions or under stress, mTORC1 is rapidly inhibited, global protein synthesis is arrested, and a cellular catabolic process known as autophagy is activated. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes multiple proteins that stimulate mTORC1 activity or subvert autophagy, but precise roles for mTORC1 in different stages of KSHV infection remain incompletely understood. Here, we report that during latent and lytic stages of KSHV infection, chemical inhibition of mTORC1 caused eukaryotic initiation factor 4F (eIF4F) disassembly and diminished global protein synthesis, which indicated that mTORC1-mediated control of translation initiation was largely intact. We observed that mTORC1 was required for synthesis of the replication and transcription activator (RTA) lytic switch protein and reactivation from latency, but once early lytic gene expression had begun, mTORC1 was not required for genome replication, late gene expression, or the release of infectious progeny. Moreover, mTORC1 control of autophagy was dysregulated during lytic replication, whereby chemical inhibition of mTORC1 prevented ULK1 phosphorylation but did not affect autophagosome formation or rates of autophagic flux. Together, these findings suggest that mTORC1 is dispensable for viral protein synthesis and viral control of autophagy during lytic infection and that KSHV undermines mTORC1-dependent cellular processes during the lytic cycle to ensure efficient viral replication.

Topics: Autophagy; Butyric Acid; Cell Line; Eukaryotic Initiation Factor-4F; Herpesvirus 8, Human; Host-Pathogen Interactions; Humans; Immediate-Early Proteins; Mechanistic Target of Rapamycin Complex 1; Sarcoma, Kaposi; Sirolimus; Trans-Activators; Virion; Virus Activation; Virus Latency; Virus Replication

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

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: Biopsy; Child; Diagnosis, Differential; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymph Nodes; Lymphadenopathy; Lymphatic Metastasis; Male; Nephrotic Syndrome; Sarcoma, Kaposi; Sirolimus

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

Solid-organ transplant recipients are at higher risk of developing Kaposi sarcoma, which is a multicentric vascular neoplasm of lymphatic endothelium-derived cells. Reducing doses of immunosuppressive drugs and switching from calcineurin inhibitors to the mammalian target of rapamycin inhibitor rapamycin have been suggested as an effective first-line treatment modality in most patients. Herein, we report a 64-year-old renal transplant recipient who developed multiple cutaneous and visceral Kaposi sarcoma lesions 2 months after transplant. The patient showed no improvement, with progression of the disease until month 15 of the suggested therapy of rapamycin.

Topics: Antibiotics, Antineoplastic; Drug Substitution; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Protein Kinase Inhibitors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

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

Kaposi᾽s sarcoma (KS) can develop in 0.06% to 4.1% of kidney transplant recipients. Here we describe a case of 50-year-old man who developed KS a few months after kidney transplantation. After transplantation, he had delayed graft function and was managed by anti-thymocyte globulin (ATG) for five days. At the discharge, his immunosuppressive therapy was prednisolone 20 mg/day, tTacrolimus (Pprograf®) 4 mg/day, and mycophenolate mofetil (MMF) 2 gr/day, while he also took Vvalcyte and diltiazem. Once diagnosed with KS, the Prograf® (tacrolimus)  was replaced by prednisolone (5 mg/day) and sirolimus (2 mg/day). Gradually the skin nodule on the patient arm disappeared, and the others nodule on the right his leg was decreased. It seems that the examination of skin should be a part of regular follow-up and dermatologist examination is recommended every 6 months.

Topics: Antibiotics, Antineoplastic; Humans; Kidney Transplantation; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

A 63-year-old African male with end stage renal disease who received a renal transplantation from his daughter after successful treatment of hepatitis C virus, type 1 genotype developed metastatic Kaposi's sarcoma and subsequently adenocarcinoma of the prostate. He was successfully treated with chemotherapy and reduction of immunosuppression and switch over to rapamycin.

Topics: Adenocarcinoma; Antineoplastic Agents; Biopsy; Black People; Drug Substitution; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Male; Middle Aged; Neoplasms, Second Primary; Prostatic Neoplasms; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tanzania; Time Factors; Treatment Outcome

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

Topics: Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Arthritis, Rheumatoid; HIV Seronegativity; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

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

Topics: Aged; Biopsy, Needle; Everolimus; Female; Follow-Up Studies; Glomerulonephritis, Membranous; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Function Tests; Sarcoma, Kaposi; Severity of Illness Index; Sirolimus; Skin Neoplasms; Treatment Outcome

Cancer in transplant recipients represents a therapeutic challenge even when the patient is already under mTOR inhibitors. A 78-year-old man received a deceased donor kidney transplant in 1993. After 6 months, he developed a multifocal cutaneous and nonvisceral Kaposi's Sarcoma while on cyclosporine immunosuppressant therapy. The patient was converted to sirolimus monotherapy in 2001 with subsequent complete recovery within 2 years. In 2007, the patient was diagnosed with an esophageal adenocarcinoma stage IIA. An esophagectomy was performed without requirement of further treatment. He has continued on sirolimus monotherapy ever since, with no other incidents and no recurrences of either tumor. In this report, we describe an interesting case of a second cancer while on immunosuppressive therapy with anticancer activity. Moreover, the present knowledge of the matter is discussed.

Topics: Adenocarcinoma; Aged; Azathioprine; Biomarkers; Cyclosporine; Drug Substitution; Esophageal Neoplasms; Esophagectomy; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Neoplasm Proteins; Neoplasms, Second Primary; Phosphorylation; Postoperative Complications; Prednisone; Protein Processing, Post-Translational; Sarcoma, Kaposi; Signal Transduction; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

With this study we aimed to research the effects of immunosuppressive drugs, their cumulative doses, and viral infections on development of malign tumors in patients who have undergone treatment for 5 years.. We examined 100 patients who underwent renal transplantation from 2004 to 2009. Patients had mycophenolate mofetil and steroid in addition to cyclosporine, sirolimus, or tacrolimus as immunosuppressive treatment. For malignancy screening, physical examination, radiologic and endoscopic screening were done, and immunosuppressive drugs and their cumulative doses, age, sex, body mass index (BMI), dialysis history, and viral infection history were investigated.. The mean age of patients was 42.03 ± 11.30 years. There were 1 colon cancer patient, 1 retroperitoneal liposarcoma, 1 renal oncocytoma, 3 Kaposi sarcoma patients treated with cyclosporine; in those treated with Tac there were 1 basal cell carcinoma, 1 Kaposi sarcoma, 2 thyroid carcinoma, 1 breast carcinoma, 1 bladder carcinoma, 1 renal cell carcinoma, and 1 colon carcinoma patients. The mean age of patients having carcinoma was statistically significant compared with those without cancer (P < .01). The prednisolone cumulative dose was significantly higher in carcinoma patients than in patients without carcinoma (P < .01).. The use of long-term chronic immunosuppressive therapy may increase the development of cancer. The risk of carcinoma increases with increasing drug dose and time period of the immunosuppressive drug. There was not a negative effect on cancer prevalence in patients with cyclosporine or tacrolimus. But the cumulative dose of steroids significantly increased malignancy occurence.

Topics: Adult; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cyclosporine; Early Detection of Cancer; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Steroids; Tacrolimus; Thyroid Neoplasms; Time Factors; Urologic Neoplasms

Dysregulation of the PI3K/Akt/mTOR pathway is one of the most frequent events in human cancer. However, the clinical benefits of PI3K/Akt/mTOR inhibitors have not yet achieved their predicted potential in many of the most prevalent human cancers. Of interest, treatment of Kaposi's sarcoma (KS) patients with rapamycin provided the first evidence of the antineoplastic activity of mTOR inhibitors in humans, becoming the standard of care for KS arising in renal transplant patients. Thus, the study of KS may provide a unique opportunity to dissect the contribution of specific mTOR downstream targets to cancer development. The KS-associated herpesvirus (KSHV) is the etiological agent for KS, and the KSHV-encoded oncogene viral-G protein-coupled receptor (vGPCR) promotes the potent activation of the PI3K-Akt-mTOR pathway by both direct and paracrine mechanisms. We focused on a direct target of mTOR, EIF4EBP1/2/3 (4EBP), which inhibits the translation of eukaryotic initiation factor 4E (eiF4E)-bound mRNAs. 4EBP phosphorylation by mTOR relieves its inhibitory activity, hence resulting in increased eiF4E-dependent mRNA translation. We developed a paracrine transformation model, recapitulating the cellular composition of KS lesions, in which vGPCR-expressing cells promote the rapid proliferation of endothelial cells, thus expressing KSHV-latent genes by the release of growth factors. Using this model, we show here that the accumulation of dephosphorylated 4EBP in response to rapamycin or by the expression of an mTOR-insensitive mutant of 4EBP1 is sufficient to disrupt the eiF4E function downstream of mTOR to a similar extent than the mTOR catalytic inhibitor Torin2 and to halt KS development. We also provide evidence that eiF4E contributes to paracrine neoplastic, signaling through the release of pro-angiogenic factors that are acting on endothelial cells, expressing KSHV-latent genes. These findings may provide a preclinical platform and the rationale for the development of novel mTOR, inhibiting agents that may selectively disrupt the mTOR-4EBP interaction for the treatment of KS and other tumor lesions, exhibiting hyperactive mTOR pathway function.

Topics: Adaptor Proteins, Signal Transducing; Antibiotics, Antineoplastic; Carrier Proteins; Cell Cycle Proteins; Cell Transformation, Viral; Eukaryotic Initiation Factors; Herpesvirus 8, Human; Humans; Oncogenes; Paracrine Communication; Phosphoproteins; Receptors, Chemokine; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases

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

Immunosuppression therapy following organ transplantation is a significant factor in the development and progression of Kaposi's sarcoma-associated herpesvirus (KSHV)-induced posttransplant Kaposi's sarcoma (KS). Switching from cyclosporine to the mTOR inhibitor rapamycin is reported to promote KS regression without allograft rejection. Examining the underlying molecular basis for this clinical observation, we find that KSHV infection selectively upregulates mTOR signaling in primary human lymphatic endothelial cells (LECs), but not blood endothelial cells (BECs), and sensitizes LECs to rapamycin-induced apoptosis. Viral transcriptome analysis revealed that while infected BECs display conventional latency, KSHV-infected LECs support a radically different program involving widespread deregulation of both latent and lytic genes. ORF45, a lytic gene selectively expressed in infected LECs, is required for mTOR activation and critical for rapamycin sensitivity. These studies reveal the existence of a unique herpesviral gene expression program corresponding to neither canonical latency nor lytic replication, with important pathogenetic and therapeutic consequences.

Topics: Apoptosis; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation, Viral; Herpesvirus 8, Human; Humans; Mechanistic Target of Rapamycin Complex 1; Mitogen-Activated Protein Kinase 1; Multiprotein Complexes; Ribosomal Protein S6 Kinases, 90-kDa; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Up-Regulation; Virus Latency

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Delayed Diagnosis; Dermatitis; Diagnostic Errors; Drug Substitution; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Postoperative Period; Prednisone; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Tacrolimus; Vinblastine

Topics: Everolimus; Female; Humans; Ileal Neoplasms; Immunosuppression Therapy; Immunosuppressive Agents; Jejunal Neoplasms; Lung Transplantation; Middle Aged; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases

Human herpesviruses (HHV) 6 and 7 are ubiquitous infections that reactivate commonly in transplant recipients. However, clinical diseases due to these viruses are reported only in 1% of solid organ transplant recipients. Fever, rash and bone marrow suppression are the most common manifestations, but symptoms of tissue invasive disease may be observed. Treatment of HHV-6 and HHV-7 disease includes antiviral therapy and cautious reduction in immunosuppression. HHV-8 is an oncogenic gamma-herpesvirus that causes Kaposi's sarcoma, Castleman's disease and primary effusion lymphomas in transplant recipients. Nonmalignant diseases such as bone marrow suppression and multiorgan failure have also been associated with HHV-8. Reduction in immunosuppression is the first line treatment of HHV-8 infection. Other alternatives for treatment, especially for HHV-8 diseases not responsive to immuno-minimization strategies, are surgery and chemotherapy. Sirolimus has been shown to be a beneficial component for the treatment of Kaposi's sarcoma and the role of antivirals for HHV-8 infection is being investigated.

Topics: Antiviral Agents; Herpesviridae Infections; Herpesvirus 6, Human; Herpesvirus 7, Human; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Organ Transplantation; Sarcoma, Kaposi; Sirolimus

Kaposi sarcoma originates from endothelial cells and it is one of the most overt angiogenic tumors. In Sub-Saharan Africa, where HIV and the Kaposi sarcoma-associated herpesvirus (KSHV) are endemic, Kaposi sarcoma is the most common cancer overall, but model systems for disease study are insufficient. Here, we report the development of a novel mouse model of Kaposi sarcoma, where KSHV is retained stably and tumors are elicited rapidly. Tumor growth was sensitive to specific allosteric inhibitors (rapamycin, CCI-779, and RAD001) of the pivotal cell growth regulator mTOR. Inhibition of tumor growth was durable up to 130 days and reversible. mTOR blockade reduced VEGF secretion and formation of tumor vasculature. Together, the results show that mTOR inhibitors exert a direct anti-Kaposi sarcoma effect by inhibiting angiogenesis and paracrine effectors, suggesting their application as a new treatment modality for Kaposi sarcoma and other cancers of endothelial origin.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Cell Proliferation; Comparative Genomic Hybridization; Disease Models, Animal; DNA, Viral; Doxorubicin; Fluorescent Antibody Technique; Herpesvirus 8, Human; Humans; Immunoenzyme Techniques; Mice; Mice, SCID; Neovascularization, Pathologic; Phosphorylation; Real-Time Polymerase Chain Reaction; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

The mammalian target of rapamycin is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mammalian target of rapamycin-dependent signaling.. Seven participants, 4 on PI-based and 3 on NNRTI-based ART, had rapamycin titrated to achieve trough concentrations of 5-10 ng/mL. Patients were monitored for safety and KS response. KS biopsies were evaluated for changes in phosphoribosomal S6 protein, and phospho-Akt expression. Interleukin 6 and vascular endothelial growth factor levels, HIV and KS-associated herpesvirus viral loads, and CD4 counts were monitored.. Despite pharmacokinetic interactions resulting in >200-fold differences in cumulative weekly rapamycin doses between participants on PI-containing and NNRTI-containing regimens, treatment was well tolerated. There were no significant changes in viral loads or cytokine levels; modest initial decreases in CD4 counts occurred in some patients. Three participants, all on PI-containing regimens and with higher rapamycin exposure, showed partial KS responses. Three of 4 subjects whose biopsies were studied at ≥day 50 showed decreased phosphoribosomal S6 protein staining.. Rapamycin seems safe in HIV-infected individuals with KS and can, in some cases, induce tumor regression and affect its molecular targets. Significant pharmacokinetic interactions require careful titration to achieve target drug trough concentrations but may be exploited to achieve therapeutic benefit.

Topics: Adult; Antibiotics, Antineoplastic; Antigens, Viral; Biomarkers, Tumor; Cytokines; Drug Therapy, Combination; Female; HIV Infections; Humans; Immunohistochemistry; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Viral Load

Iatrogenic Kaposi sarcomas (KS) in organ transplant recipients are often treated by switching immunosuppressive therapy to an mTOR inhibitor, such as sirolimus or everolimus, as these have immunosuppressive as well as anti-tumor effects. We report on an 80-year-old male patient who developed a disseminated cutaneous KS during therapy with prednisone and azathioprine for myasthenia gravis. After discontinuation of azathioprine therapy and despite continuing therapy with cortisone, the KS progressed and autoantibody levels against the nicotinic acetylcholine receptor increased. During the administration of everolimus, a long-term near-complete remission of KS and a decrease in autoantibodies took place. This case study illustrates that even in non-organ transplant patients with iatrogenic KS, switching to immunosuppressive therapy using an mTOR inhibitor can be beneficial.

Topics: Aged, 80 and over; Everolimus; Humans; Immunosuppressive Agents; Male; Myasthenia Gravis; Remission Induction; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Aged; Angiomyolipoma; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lymphoma, Non-Hodgkin; Nephrectomy; Prednisone; Sarcoma, Kaposi; Sirolimus; Splenectomy; Tomography, X-Ray Computed; Vincristine

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

The incidence of Kaposi sarcoma (KS) has substantially increased among immunocompromised patients, suggesting a role for immunosuppressive drugs. The aim of this study was to evaluate the incidence, features, and outcome of KS among 307 kidney transplantation patients at our center between January 1994 and June 2010. During the study period, the 10 patients who developed KS (3.25%) showed a mean age at transplantation of 35.8 ± 8.7 years (range, 22 to 49 years). The mean interval between transplantation and occurrence of KS was 24.7 ± 21.36 months (range, 6 to 64 months). The mean time of antithymocyte globulin induction was 9.5 days (range, 6 to 13 days). KS was restricted to the skin in 7 cases, among which, one presented with associated Hodgkin lymphoma. Visceral involvement (one lung and one colon) was observed in two cases. One patient presented with a gastric KS without skin lesions. Immunosuppressive treatment was reduced, then withdrawn in three cases, resulting in regression of KS a few weeks later, but with graft loss requiring hemodialysis at 1, 3 and 4 months. Among the remaining 7 cases, we stopped mycophenalate mofetil (MMF) and switched from calcineurin inhibitors to sirolimus. Allograft function remained stable after the switch. Only one patient who already had allograft dysfunction due to biopsy-proven chronic allograft nephropathy. Deteriorated progressively, undergoing hemodialysis at 2 years after KS diagnosis. In conclusion, we observed a relatively high incidence of KS among our cases. The introduction of sirolimus resulted in complete regression of KS lesions with preserved graft function.

Topics: Adult; Calcineurin Inhibitors; Colonic Neoplasms; Drug Substitution; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Lung Neoplasms; Male; Middle Aged; Renal Dialysis; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Stomach Neoplasms; Time Factors; Treatment Outcome; Tunisia

  Development of KS in pediatric liver transplant recipients is a rare entity and has dismal prognosis. Latent HHV-8 infection, immunosuppression, and genetic predisposition are possible etiological factors. Decreasing the dose or cessation of immunosuppressive drugs, switching to sirolimus with antiproliferative and antitumor properties, and different chemotherapeutic regimens are the current therapeutic strategies. We herein report a pediatric liver transplant recipient who developed generalized KS at post-transplant fifth month. The disease had an aggressive course despite the highly toxic chemotherapy. On the other hand, a prompt and durable response was provided by paclitaxel with tolerable side effects. The patient is now free of disease for at least 24 months and healthy with good graft function under sirolimus therapy as maintenance immunosuppression. Instead of highly toxic chemotherapy, paclitaxel can be used as therapeutic option in cases with generalized disease and in those who are unresponsive to conventional chemotherapy. However, new studies are needed to assess the efficacy of the paclitaxel therapy in KS in the liver transplant recipients.

Topics: Antineoplastic Agents; Female; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Infant; Liver Failure; Liver Transplantation; Lymphoproliferative Disorders; Paclitaxel; Prognosis; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

Infection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis.. In latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions.. These results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post-transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection.

Topics: Antibiotics, Antineoplastic; B-Lymphocytes; Cell Line; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Sarcoma, Kaposi; Sirolimus; TOR Serine-Threonine Kinases; Virus Replication

Topics: Drug Substitution; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Living Donors; Male; Middle Aged; Patient Readmission; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

Current treatment of Kaposi's sarcoma is reduction of immunosuppression with or without addition of mammalian target of rapamycin inhibitors (mTORi). Akt signalling plays a central role in oncogenesis of Kaposi's sarcoma. We describe a case of multifocal Kaposi's sarcoma in a renal allograft recipient, which showed unsatisfactory early response to immunosuppression reduction along with everolimus therapy but completely resolved after adding leflunomide. mTORi impair Kaposi's sarcoma oncogenesis by inhibiting mTOR downstream from the Akt signalling. Leflunomide inhibits Akt phosphorylation. This synergistic effect may be beneficial in treatment of Kaposi sarcoma and needs to be explored in trials.

Topics: Antineoplastic Agents; Everolimus; Humans; Immunosuppressive Agents; Isoxazoles; Kidney Diseases; Kidney Transplantation; Leflunomide; Male; Middle Aged; Proto-Oncogene Proteins c-akt; Sarcoma, Kaposi; Sirolimus; Transplantation, Homologous; Treatment Outcome

Topics: Antibiotics, Antineoplastic; Bone Marrow Transplantation; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Lung Neoplasms; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Transplantation, Homologous

A 38-year-old Afro-Caribbean woman, who was pre-dialysis with polycystic kidney disease, received a live-donor kidney transplant from her 55-year-old mother. This study documents her imunosuppression therapy including resolution of an oral Kaposi's sarcoma and explores the many underlying problems with converting to an mTOR inhibitor.

Topics: Adult; Female; Graft Rejection; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Mouth Neoplasms; Polycystic Kidney Diseases; Sarcoma, Kaposi; Sirolimus

Kaposi's sarcoma (KS) is an infrequent vascular neoplasm commonly diagnosed as an isolated cutaneous lesion that can involve other organs. So far, there are no data in the literature about the development of KS after intestinal transplant.. In this study, the authors describe a case of "visceral KS" with pulmonary and intestinal involvement and perform a systematic literature review of case reports and single-center series identified in MEDLINE.. This case was a 42-year-old man, diagnosed with visceral KS 9 months after receiving an isolated intestinal transplant. He was successfully treated with a combination of sirolimus and liposomal doxorubicin and achieved an 18-month disease-free survival. A total of 54 cases from 27 manuscripts and the present case were analyzed in this study. The mean time from transplant to diagnosis was 17.2 months. Lungs and gastrointestinal tract were the main organs involved. Immunosuppressants were discontinued in two of the three (66.7%) cases, and sirolimus was added in eight cases. Doxorubicin was used in 12 cases. In a univariate analysis, the use of Tacrolimus, type of transplant, and presence of cutaneous KS seem to be the significant predictors of response to therapy and survival; the addition of doxorubicin showed a reduction in graft loss.. Treatment of KS in posttransplant patients should be designed aiming to obtain a complete response, irrespective of the organ affected. Only recipients who are able to achieve a sustained response would be able to obtain long-term disease-free survival.

Topics: Adult; Antibiotics, Antineoplastic; Disease-Free Survival; Doxorubicin; Humans; Immunosuppressive Agents; Intestines; Male; Recurrence; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

The Id-proteins are a family of four related proteins implicated in the control of differentiation and cell-cycle progression. Down-regulation of Id-gene expression is essential for the differentiation of several cell types. In addition, deregulated Id2 activity inhibits the Rb tumor suppressor pathway and promotes the expression of vascular endothelial growth factor (VEGF). Several members of VEGF family could be involved in Kaposi's sarcoma (KS) development and progression. Lymphatic vascular endothelial hyaluronan receptor-1 (LYVE-1) is the first marker of lymphatic endothelial competence during development in the mature vasculature, and is also expressed on KS spindle cells. Rapamycin (RAPA), an immunosuppressive drug, has been shown to reverse KS growth and to reduce tumor angiogenesis. We evaluate, in transplantation-associated KS and in cultured KS-cells the RAPA effect on Id2 and on de novo lymphangiogenesis. Markers of lymphatic-endothelial-cells (VEGFR-3, LYVE-1) and Id2, expressed at low levels within the normal skin, were up-regulated in KS and returned to normal levels after RAPA introduction. The association between Id2 and lymphangiogenesis is suggested by co-localization of Id2, VEGFR-3 and LYVE-1. RAPA inhibition on Id2 expression was confirmed in vitro in KS-cells, both in basal conditions and upon stimulation with VEGF. In conclusion, our data would suggest a novel molecular mechanism for the antineoplastic effects of RAPA in posttransplant KS.

Topics: Cell Line, Tumor; Disease Progression; Female; Gene Expression Regulation; Humans; Inhibitor of Differentiation Protein 2; Male; Middle Aged; Sarcoma, Kaposi; Signal Transduction; Sirolimus; Skin Transplantation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-3; Vesicular Transport Proteins

Nowadays cancer represents the second main cause of death in renal transplant patients with normal function of the graft. The incidence is 10 to 20 times higher than normal population. Calcineurin inhibitor therapy contributes to the increase in the development of neoplasia. Important evidence could bring a preventive effect of mammalian target of rapamycin in skin cancer, Kaposi's sarcoma, and renal cell carcinoma.

Topics: Aged; Calcineurin Inhibitors; Carcinoma, Renal Cell; Cause of Death; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Neoplasms; Postoperative Complications; Protein Kinases; Risk Factors; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases

Topics: Antibiotics, Antineoplastic; Castleman Disease; Herpesvirus 8, Human; Humans; Liver Transplantation; Lymphoma, Primary Effusion; Protein Kinases; Sarcoma, Kaposi; Sirolimus; T-Lymphocytes; TOR Serine-Threonine Kinases; Transplantation Immunology

A patient with human immunodeficiency virus infection and end-stage renal disease received a renal transplant. At the time of surgery, the patient was on quadruple antiretroviral therapy (lamivudine, zidovudine, and amprenavir/ritonavir). Immunosuppression was initiated with basiliximab, corticosteroid, mycophenolate mofetil, and a single 0.5 mg dose of tacrolimus. In the following days, an increase in tacrolimus concentration was observed with a peak of 37 ng/mL. Tacrolimus half-life was 6.5 days and tacrolimus maintenance dose was 0.5 mg every 4 days. Eleven months later, the patient had developed Kaposi sarcoma. Tacrolimus was replaced by sirolimus (first dose 1 mg), and the patient was stabilized with 1.5 mg of sirolimus once a week. Increased tacrolimus half-life and increased dose interval of sirolimus and tacrolimus were due to CYP3A4/5 and/or P-glycoprotein inhibition by protease inhibitors. Close monitoring is required in the management of tacrolimus and sirolimus dosing regimens when combined with ritonavir boosted HIV-1 protease inhibitors.

Topics: Drug Interactions; Half-Life; HIV Infections; HIV Protease Inhibitors; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Tacrolimus

SRL is a new and potent immunosuppressive agent that has been successfully introduced in organ transplantation. In contrast to other immunosuppressive agents, SRL has a potent antitumor activity both in vitro and in vivo. Herein, we report a child with Kaposi's sarcoma that was diagnosed 30 months after LDLT and treated successfully with only conversion to SRL monotherapy. KS regressed completely at the end of the first month and remained in remission during 28 months follow-up.

Topics: Antibiotics, Antineoplastic; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Infant; Liver Transplantation; Living Donors; Sarcoma, Kaposi; Sirolimus; Tacrolimus; Treatment Outcome

Kaposi's sarcoma (KS) is associated with solid-organ transplantation, but is extremely rare after lung transplantation. In this report, we describe two unique cases of lung transplant recipients who developed KS in the lung allograft and were treated with sirolimus and liposomal doxorubicin. One patient survived 12 months after the diagnosis of KS; the other survived 3 months after diagnosis and was found to have concomitant EBV-negative, HHV-8-positive B-cell lymphoma. We demonstrate a partial response of pulmonary KS to reduced immunosuppression and the initiation of sirolimus in one patient, as well as an association between increasing HHV-8 viremia and progression of pulmonary KS. Our report highlights the importance of secondary malignancies in patients with transplant-related KS and supports the association between HHV-8 infection and EBV-negative PTLD.

Topics: Adult; Doxorubicin; Fatal Outcome; Herpesvirus 8, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Neoplasms; Lung Transplantation; Male; Middle Aged; Radiography; Sarcoma, Kaposi; Sirolimus; Tissue Donors; Transplantation, Homologous; Transplants; Viral Load

Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathologic angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus-encoded G protein-coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here, we show that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the up-regulation of several Akt proliferative and survival pathways. However, use of a novel dual phosphatidylinositol 3-kinase alpha (PI3Kalpha)/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathologic angiogenesis, our results further provide the basis for the early assessment of PI-103 as an antiangiogenic chemotherapeutic.

Topics: Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Apoptosis; Cell Line; Cell Proliferation; Endothelial Cells; Furans; Immunosuppressive Agents; Mice; Neoplasm Transplantation; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyridines; Pyrimidines; Receptors, G-Protein-Coupled; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Homologous

Kaposi's sarcoma (KS) is a vascular neoplasm typically observed in the immunocompromised patient populations, such as acquired immunodeficiency syndrome or transplant patients. KS can appear simultaneously at multiple sites as red to purple, maculo-papular or nodular cutaneous lesions sometimes showing a visceral extension. Sirolimus, an immunosuppressive agent with potent antitumor activity, has been effective in combating post-transplant KS. However, an aggressive regimen of immunosuppression for therapy of severe acute rejection episodes may abolish the antitumor effects of sirolimus. The following is a description of KS development under immunosuppressive therapy with sirolimus, and the successful treatment of KS lesions utilizing the topical application of imiquimod 5% cream, an immune response modifier.

Topics: Aged; Aminoquinolines; Antineoplastic Agents; Graft Rejection; Herpesvirus 8, Human; Humans; Imiquimod; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Sarcoma, Kaposi; Sirolimus

Topics: Adult; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Iatrogenic Kaposi's sarcoma (KS) has been reported in patients who use immunosuppressive regimens for the treatment of autoimmune disorders, malignant neoplasms, and organ transplant rejection. However, iatrogenic KS in the setting of pemphigus vulgaris (PV) has been infrequently observed. The conventional treatment strategy for iatrogenic KS has focused on reducing immunosuppression, which carries a poor prognosis owing to a substantial risk for exacerbation of the primary disease.. A 49-year-old man developed KS on his wrist after 2 years of long-term immunosuppressive therapy with prednisone, methotrexate, and dapsone for well-controlled PV. Three months after the substitution of methotrexate with sirolimus, the KS gradually resolved. With the patient on a maintenance regimen of sirolimus, in conjunction with low-dose prednisone and dapsone therapy, KS and PV have remained in remission, without further recurrence, during a 24-month follow-up period.. The present case introduces a novel therapy for this patient population, highlighting the efficacy of sirolimus in treating iatrogenic KS without sacrificing the immunosuppression necessary to maintain control of PV.

Topics: Humans; Iatrogenic Disease; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Pemphigus; Retreatment; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Topics: Antibiotics, Antineoplastic; HIV Infections; Humans; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

Topics: Adult; Female; Glomerulonephritis; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prednisone; Reoperation; Sarcoma, Kaposi; Secondary Prevention; Sirolimus

Renal transplant recipients are susceptible to Kaposi's sarcoma (KS) because of treatment with immunosuppressive drugs. Sirolimus, a new immunosuppressive agent, has been successfully used for immune-suppression in kidney transplant recipients. Several studies have shown the potential role of sirolimus to inhibit progression of KS in kidney-transplant recipients. This report details a kidney-transplant recipient with cutaneous KS who had a complete remission in response to sirolimus therapy.

Topics: Adult; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms

Topics: Angiogenesis Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Neoplasms; Organ Transplantation; Sarcoma, Kaposi; Sirolimus; Tacrolimus; United States

Imatinib is a tyrosine-kinase inhibitor; for which there is limited information regarding its effects on AIDS Kaposi's sarcoma and none in patients with transplant-associated Kaposi's sarcoma. Sirolimus, an immunosuppressive drug used for kidney transplant, exhibits antiangiogenic activity related to impaired production of VEGF (vascular endothelial growth factor), clinical benefit has been reported in Kaposi's sarcoma associated with renal graft.. Here we report a case of an 80 year old male, who developed Kaposi's Sarcoma nine months after receiving a living non-related donor kidney transplant at age 74. Three years after treatment with different chemotherapeutic agents for progressive cutaneous Kaposi's Sarcoma with no visceral involvement, he was prescribed Imatinib (200 mg/day for two weeks followed by 400 mg/day) after four weeks of treatment he developed anasarca, further progression of KS and agranulocytosis. Imatinib was discontinued and there was significant clinical recovery. One year later his immunosuppressive therapy was changed to Sirolimus and regression of the Kaposi's sarcoma occurred.. The lack of benefit and severe toxicity associated with the use of Imatinib in this patient should alert clinicians of potentially adverse consequence of its use in patients with transplant associated Kaposi's sarcoma. On the other hand the positive response seen in this patient to Sirolimus even after a long evolution of Kaposi's sarcoma, multiple chemotherapy regimens and extensive cutaneous disease further suggest it therapeutical utility for transplant associated Kaposi's sarcoma.

Topics: Aged, 80 and over; Benzamides; Biopsy, Needle; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Humans; Imatinib Mesylate; Immunohistochemistry; Kidney Failure, Chronic; Kidney Transplantation; Male; Neoplasm Staging; Piperazines; Pyrimidines; Retreatment; Risk Assessment; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

The incidence of Kaposi's sarcoma among recipients of solid organs is about 500 times the rate in the general population, suggesting a role for immunosuppression in its development. On the basis of these findings, we investigated the impact of sirolimus on cutaneous and disseminated visceral Kaposi's sarcoma in a renal-transplant recipient. The introduction of sirolimus in this patient allowed complete regression of Kaposi's sarcoma (cutaneous and visceral) with preservation of excellent renal function. Meanwhile, in view of the available observational reports, we think that sirolimus should be included in the standard treatment for Kaposi's sarcoma after transplantation, to permit remission of the sarcoma (both cutaneous and visceral) while preserving the renal function.

Topics: Adult; Antibiotics, Antineoplastic; Humans; Immunosuppression Therapy; Kidney Transplantation; Male; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Stomach Neoplasms

The incidence of Kaposi's sarcoma (KS) is higher in organ transplant recipients. The lesions are mainly cutaneous and isolated visceral involvement is rare. We herewith report a 38-year-old male patient, who underwent a cadaveric donor renal transplantation for chronic interstitial nephropathy. His immunosuppression protocol consisted of corticosteroids, tacrolimus and mycophenolate mofetil. Twenty-five months later, he presented with diarrhea and epigastric pain. An upper gastrointestinal endoscopy revealed an ulcer in the body of the stomach. Histological examination coupled with immunohistochemistry was suggestive of KS. Detailed examination did not show any skin lesions. Computed tomography of the chest revealed multiple bilateral lung micronodules. The patient tested positive for anti-Herpes Human Virus (HHV8) antibodies. Tacrolimus and mycophenolate mofetil were withdrawn and rapamycin was introduced. This resulted in a regression of both stomach and pulmonary KS. One-year later, the patient developed an episode of acute rejection, which was successfully treated with bolus steroids. Our case suggests that rapamycin-based immunosuppression offers a promising approach to the management of post-transplant KS, particularly with visceral involvement.

Topics: Adult; Biopsy; Diagnosis, Differential; Endoscopy, Gastrointestinal; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Neoplasms; Male; Sarcoma, Kaposi; Sirolimus; Stomach Neoplasms; Tomography, X-Ray Computed

The inhibition of mTOR is a target for anticancer drugs in posttransplant malignancies. The influence of conversion to sirolimus after malignancy diagnosis was investigated on patient and renal allograft survivals. The 20 renal allograft recipients (4 women, 16 men) of ages 26 to 73 years (mean, 59 years) developed malignancies within 6 to 172 months (mean, 53 months) after transplantation. Three patients developed posttransplant lymphoproliferative disease (PTLD); four, Kaposi sarcoma, three, lung cancer; two, malignant melanoma; two, breast cancer; two, renal cell carcinoma; one, Merkel cell carcinoma; one, cutaneous T-cell lymphoma; one, larynx cancer; and one, gingival cancer. After tumor diagnosis, calcineurin inhibitors, azathioprine, or mycophenolate mofetil (MMF) were discontinued abruptly and sirolimus introduced (2 mg/d; target trough level, 4.0 to 8.0 ng/mL). Prednisone was maintained. The observation time of sirolimus therapy was 4 to 48 months (mean, 14 months). Two patients with PTLD (large B-cell lymphoma) and four with Kaposi sarcoma had full regressions. Eleven patients (larynx cancer, melanoma, breast cancer, T-cell lymphoma, renal cell carcinoma, Merkel cell carcinoma, and skin lymphoma) in addition to sirolimus therapy, underwent oncologic treatment, namely, surgery and/or chemotherapy. Six patients died from disseminated malignancy 4 to 9 months after conversion. One patient with T-cell lymphoma lost his graft; in the remaining patients, serum creatinine level was stable. In conclusion, Conversion to sirolimus resulted in regression of large B-cell lymphoma and Kaposi sarcoma. In patients with advanced or disseminated malignancy, the tumors progressed. Graft function was preserved after conversion to sirolimus.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Neoplasms; Postoperative Complications; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Transplantation, Homologous

The risk of Kaposi's sarcoma (KS) is increased after organ transplantation. Management of KS in the cardiac transplant population may be difficult because reduction of immunosuppression is often not practical. This report describes a case of KS occurring in the early post-transplant period. Modification of immunosuppression with the use of sirolimus led to tumor regression for 24 months, but with subsequent localized progression of disease.

Topics: Adult; Heart Transplantation; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Lung Neoplasms; Male; Myocardial Ischemia; Postoperative Period; Sarcoma, Kaposi; Sirolimus

Topics: Adult; Antibiotics, Antineoplastic; Humans; Kidney Transplantation; Male; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Failure

Kaposi's sarcoma (KS) is an angioproliferative neoplasia associated with human herpesvirus 8 (HHV-8) infection. HHV-8 generates KS by means of the secretion of vascular endothelial growth factor (VEGF) andup-regulation of VEGF receptor, KDR, in endothelial cells. We report a case of KS in a 72-year-old male with a renal transplant who had received immunosuppressant drugs including sirolimus, mycophenolate mofetil, tacrolimus and steroids. KS developed 11 months after transplantation, in relation to deep venous thrombosis and withdrawal of sirolimus due to toxicity. Multiple purple papules and nodules were observed exclusively in the limb affected by thrombosis. Diagnosis of KS was confirmed by biopsy. Progressive withdrawal of prednisone was accompanied by full remission of the tumour. The thrombosis and withdrawal of sirolimus may have acted as cofactors in the development of KS, favouring the activation of the VEGF/KDR autocrine loop. Our experience contributes to further evidence that sirolimus may protect against KS.

Topics: Aged; Humans; Immunosuppressive Agents; Kidney Transplantation; Leg; Male; Sarcoma, Kaposi; Sirolimus; Venous Thrombosis

This retrospective study aimed to evaluate the benefit of switching from calcineurin inhibitors (CnI) to sirolimus in posttransplant Kaposi's sarcoma (KS). Fourteen patients monitored in five French departments who had developed posttransplant KS were switched from CnI to sirolimus either abruptly (n=9) or progressively (n=5) with trough levels 5-12 ng/mL. Two patients had a complete remission, eight a partial response, and five no significant improvement of KS. The mean time to response was 3.9 months. After a mean follow-up of 16 months, 3 partial responders, with previous severe and refractory KS, suffered again from KS progression despite the lack of concomitant infectious or neoplastic event. These relapses occurred 5-9 months after switching. The tolerance of sirolimus has been excellent except for in one patient who developed severe interstitial pneumonitis. Sirolimus is usually useful in the management of posttransplant KS. It may be, however, ineffective or transiently effective in some patients with severe KS. Prospective studies with pharmacodynamic evaluation are important in order to better assess the duration of responses and the mechanisms of primary and acquired drug resistance.

Topics: Adult; Aged; Calcineurin Inhibitors; Creatinine; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sarcoma, Kaposi; Sirolimus; Time Factors; Treatment Outcome

Kaposi's sarcoma (KS) is a recognised complication following kidney transplantation, but the incidence varies according to the geographical area. Although it is a rare tumour, its incidence increases dramatically after solid-organ transplantation. The immunosuppressive medications reactivate human herpes virus 8, which has been proposed as the offending agent. The usual treatment of KS is to reduce immunosuppression, chemotherapy and radiotherapy. Nevertheless, the mortality still remains considerably high and has been reported between 8 and 14%. Sirolimus (SRL) has properties which may be useful in the management of some posttransplant tumours such as KS. We report a renal transplant patient with KS, who had multiple relapses after radiotherapy but responded well to the change of immunosuppression from cyclosporine to SRL.

Topics: Cyclosporine; Female; Herpesvirus 8, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; Treatment Outcome

The Kaposi's sarcoma-associated herpesvirus (KSHV), the infectious causative agent of Kaposi's sarcoma (KS), encodes a G protein-coupled receptor (vGPCR) implicated in the initiation of KS. Here we demonstrate that Kaposi's sarcomagenesis involves stimulation of tuberin (TSC2) phosphorylation by vGPCR, promoting the activation of mTOR through both direct and paracrine mechanisms. Pharmacologic inhibition of mTOR with rapamycin prevented vGPCR sarcomagenesis, while overactivation of this pathway was sufficient to render endothelial cells oncogenic. Moreover, mice haploinsufficient for TSC2 are predisposed to vascular sarcomas remarkably similar to KS. Collectively, these results implicate mTOR in KS initiation and suggest that the sarcomagenic potential of KSHV may be a direct consequence of the profound sensitivity of endothelial cells to vGPCR dysregulation of the TSC2/mTOR pathway.

Topics: Animals; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Endothelial Cells; Herpesvirus 8, Human; Humans; Mice; Mice, Nude; Mice, Transgenic; Oncogene Protein v-akt; Paracrine Communication; Phosphorylation; Protein Kinases; Receptors, Chemokine; Sarcoma, Kaposi; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Viral Proteins

Topics: Antibiotics, Antineoplastic; HIV Seronegativity; Homosexuality, Male; Humans; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

The conversion to sirolimus treatment is recently indicated as an effective therapy of Kaposi's sarcoma (KS) in transplant patients. We present two treatment modalities in patients with KS and recurrence of the disease after increasing sirolimus dose. Among 1034 renal transplants performed at our center, three (0.3%) suffered from KS. Initial immunosuppression consisted of cyclosporine, azathioprine and prednisone in one patient; and tacrolimus, mycophenolate mofetil and prednisone in two patients. KS symptoms appeared within one year post-transplantation. Two patients developed cutaneous tumor; one disseminated disease, including the skin, mediastinal lymph nodes and both lungs. After histological confirmation of KS immunosuppression was minimized: Two were converted to sirolimus (1-2 mg/day, level 5-8 ng/ml) treatment; the third patient discontinued tacrolimus and was administered 1 g/day mycophenolate mofetil. Gradual regression of KS was observed in all the patients. In one patient, 8 months after regression of lung KS, the dose of sirolimus was increased to 2 mg/day (level raised to 13.8 ng/ml). Recurrent disease developed afterwards involving diffuse interstitial infiltrates with nodular changes in both lungs. For the second time the dose of sirolimus was reduced to 1 mg/day (level 4-5 ng/ml) and lung lesions regressed 5 months later. Renal function was stable (creatinine 1.3-1.9 mg/dl) in all patients, 24 months from KS onset.. treatment by low sirolimus or mycophenolate mofetil doses caused regression of KS. Recurrence of KS after increasing sirolimus dose suggests that regression of KS is a result of diminished immunosuppression, not the direct antineoplastic effect of sirolimus. Careful maintenance of low sirolimus levels is suggested.

Topics: Drug Therapy, Combination; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Sarcoma, Kaposi; Sirolimus

Topics: Antibiotics, Antineoplastic; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Organ Transplantation; Risk Factors; Sarcoma, Kaposi; Sirolimus

Kaposi's sarcoma (KS) is a rare complication of renal transplantation in Poland (in our center 2 of 1000 patients). Neovascularization (typical for KS) is promoted by KS-related vascular endothelial growth factor (t-r-VEGF). Sirolimus may reduce t-r-VEGF synthesis and inhibit PI3K-p70S6 kinase of endothelial cells. Two men, 58 and 51 years old, were transplanted in 2002. Initial immunosuppression consisted of cyclosporine, azathioprine, and prednisone. In the second patient, at the week 8 the immunosuppression was switched to tacrolimus and mycophenolate mophetil. KS symptoms appeared on hard palate and skin in month 7 in both patients. In the first patient, the X-ray showed enlargement of mediastinal lymph nodes and diffuse interstitial infiltrates with nodular changes in both lungs. Serum creatinine of the first patient was increased from 1.6 to 1.9 mg/dL, while in the second it remained stable (approximately 2.0 mg/dL). Since confirmation of KS immunosuppression has been minimized in both patients; all drugs except prednisone were withdrawn, and sirolimus was introduced (1-2 mg/24 hours blood level 5-8 ng/mL). Within a month the progression of lung and skin disease ceased, and patients' conditions began to improve with lung opacities regressing, the biggest skin lesions diminishing and smaller ones disappearing. Within 1 year renal function improved. Our observation suggests that sirolimus-based immunosuppression proffers the possibility of KS regression with concomitant renal function preservation among renal graft recipients. It is difficult to ascertain whether KS regression may be attributed to sirolimus treatment or to the reduced overall immunosuppression.

Topics: Antibiotics, Antineoplastic; Cadaver; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sarcoma, Kaposi; Sirolimus; Tissue Donors; Treatment Outcome

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Neoplasms; Sarcoma, Kaposi; Sirolimus

Topics: Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Sarcoma, Kaposi; Sirolimus; Skin; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors

Topics: Aged; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Remission Induction; Sarcoma, Kaposi; Sirolimus

Topics: Aged; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Liver Transplantation; Male; Podocytes; Proteinuria; Sarcoma, Kaposi; Sirolimus; Vascular Endothelial Growth Factor A

The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has been related to the KS herpes virus and the permissive effect of immunosuppressive therapy. We postulated that conversion to SRL in renal recipients with KS favored regression of KS lesions without increasing the risk of graft rejection.. In this study we performed a retrospective chart review of 7 caucasian renal transplant recipients affected by KS to determine demographic data, etiology of ESRD, immunologic risk factors, immunosuppressive treatment, KS disease follow-up, and renal function before and after SRL conversion.. All seven patients were under calcineurin inhibitor treatment at the onset of KS which was limited to the skin, without regression despite attempts to minimize immunosuppression. After conversion to SRL, six patients showed progressive regression of KS lesions, with only hyperpigmented atrophic cutaneous lesions remaining after a mean time of 8.1 months (2-18 months). The seventh patient has completed 9 months follow-up with a near complete regression of KS lesions. One patient returned to hemodialysis after 13 months following irreversible acute renal failure not directly related to SRL conversion; in the other six, renal function was stable. The mean serum creatinine was 1.87 +/- 0.64 versus 1.74 +/- 0.68 mg/dL, pre-conversion versus the end of follow up, respectively. Mean SRL blood level was 9.2 +/- 2.0 ng/mL.. After SRL conversion, patients with KS showed progressive regression without an increased risk of acute rejection. SRL offers a promising approach to the management of posttransplantation KS and probably other malignancies in organ transplant recipients.

Topics: Animals; Calcineurin Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Sarcoma, Kaposi; Sirolimus

The prevalence of Kaposi's sarcoma (KS) is much greater in organ transplant recipients than it is in the general population. Its etiology appears to be related to geographic, genetic, and viral factors. Treatment of transplant-related KS has, until now, consisted mainly of reduction of, or withholding of, immunosuppression, often with deleterious effects on both graft and patient survival. In recent years, the immunosuppressive drug, sirolimus, has been demonstrated as possessing anti-neoplastic properties in both in vitro and animal models. In view of these properties and some preliminary clinical experience, we postulated that sirolimus would be beneficial in our patients who developed transplant-related KS. Here, we report the first case of a patient with both cutaneous and visceral KS who was successfully treated in the Middle East by conversion from a cyclosporine-based to a sirolimus-based immunosuppression regimen. The KS regressed completely within a few months after the conversion. The chronologic events and the extensive documentation, which included repeat computed tomography scans, are very suggestive of a selective anti-neoplastic effect of sirolimus.

Topics: Antineoplastic Agents; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Remission Induction; Sarcoma, Kaposi; Sirolimus

The increased incidence of Kaposi's sarcoma (KS) in organ transplantation has been related to the KS herpesvirus and the permissive effect of immunosuppressive therapy. Calcineurin inhibitors are the cornerstone of immunosuppression in organ transplantation, although they could promote tumor progression. In contrast, sirolimus, a new immunosuppressive agent, exhibits potent antitumor activity. We postulated that conversion from cyclosporine to sirolimus in patients with KS could favor regression of KS lesions without increasing the risk of graft rejection. Two renal transplant recipients with KS underwent conversion from cyclosporine to sirolimus. Both patients showed complete regression of KS lesions and excellent clinical and functional results. Sirolimus offers a new and promising approach to the management of posttransplantation KS and probably to other types of malignancies in organ transplant recipients.

Topics: Aged; Antibiotics, Antineoplastic; Cyclosporine; Diabetic Nephropathies; Glomerulonephritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Postoperative Complications; Sarcoma, Kaposi; Sirolimus