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Purpose: Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness., Experimental Design: A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness., Results: ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness., Conclusions: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients., (©2024 The Authors; Published by the American Association for Cancer Research.)

Epithelioid hemangioendothelioma is an ultra-rare cancer driven by YAP-CAMTA1 fusion. Based on the link of the fusion to the MEK pathway, SARC33 was performed. It is a phase 2 trial examining trametinib that missed its primary objective by RECIST but demonstrated patient-reported outcome benefits in improved pain. See related article by Schuetze et al., p. 4584., (©2024 American Association for Cancer Research.)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

Purpose: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacologic tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE., Experimental Design: TC is a transcriptional coregulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated., Results: Basal TC remained "immobile" in the nucleus; administration of cyclin-dependent kinase (CDK) inhibitors such as CGP60474 and dinaciclib (Dina) mobilized TC. "Mobile" TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC., Conclusions: The CDK inhibitor Dina exhibited antitumorigenic properties both in vitro and in vivo in EHE models. Dina has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing Dina for the treatment of EHE., (©2024 American Association for Cancer Research.)

Epithelioid hemangioendothelioma (EHE) is a remarkably rare tumor arising from endothelial cells that is classified as a vascular tumor in the WHO classification. The tumor is predominantly characterized by the presence of fusion genes, such as WWTR1-CAMTA1 or YAP1-TFE3, with a minority of cases exhibiting other rare fusion genes. EHE exhibits a broad age of onset, typically presenting at ~50 years, but it is not uncommon in pediatric populations. It manifests in a variety of organs, including the liver, lung, soft tissue and bone. Initial multiple-organ involvement is also observed. The tumor's biological behavior and prognosis vary substantially based on the primary site of manifestation. From a therapeutic perspective, initial active surveillance might be considered in selected cases, although surgical intervention remains the mainstay of treatment, especially for localized single-organ involvement. Chemotherapy is administered to patients with progressive unresectable tumors. Recent advances in the biological analysis of EHE fusion genes have elucidated their diverse functions. Additionally, next-generation sequencing has facilitated the identification of other mutations beyond the fusion genes. These continuous efforts to understand the biology of the fusion genes themselves and/or the dysregulated signaling by fusion genes are expected to lead to the development of novel therapeutic strategies for EHE. This article aims to provide a comprehensive review of EHE, encompassing its historical context, clinical manifestations, molecular biology and the current state of treatment., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Epithelioid hemangioendothelioma is a rare vascular malignancy, and currently, there is no standard treatment regimen for this disease and existing treatment options have limited efficacy. In this case report, we present a patient with lung and lymph node metastases from prostate epithelioid hemangioendothelioma who achieved a significant partial response. This was accomplished through alternating nivolumab therapy with ipilimumab and liposomal doxorubicin, resulting in a progression-free-survival more than 6 months to date. The treatment was well-tolerated throughout. Our report suggests that dual immunotherapy alternating with anti-PD-1antibody plus doxorubicin may be a potential treatment modality for epithelioid hemangioendothelioma. However, larger sample studies are necessary to ascertain the effectiveness of this treatment strategy and it is essential to continue monitoring this patient to sustain progression-free survival and overall survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Ye, Yang, Li, Huang, Zhou, Feng, Liu and Xie.)

Abstract: Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, is an unusual vascular proliferation that tends to manifest in the head and neck region. Its occurrence on the penis is rare, with only scarce reported cases in the literature. The histopathological examination of this condition poses a challenge because it shares similarities with other entities, such as epithelioid hemangioendothelioma, epithelioid angiosarcoma, cutaneous epithelioid angiomatous nodule, or Kaposi sarcoma (KS). The infrequency of EH in penile locations underscores the need for accurate diagnostic differentiation and tailored treatment strategies for this atypical presentation. This case report highlights a rare instance of multifocal penile EH. The patient's lesions exhibited distinctive histopathologic features, with extensive eosinophilic infiltration, presence of necrosis, and infiltration to subcutaneous fat. The patient was treated with doxorubicin, a chemotherapy drug, with a very good response. This successful therapeutic outcome underscores the potential efficacy of doxorubicin in the management of multifocal penile EH. The comprehensive analysis of this case contributes to our understanding of the clinical presentation, histopathologic features, and treatment modalities for this rare penile tumor, providing valuable insights for future clinical considerations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases., Methods and Results: Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patient's tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer., Conclusion: The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine., (© 2023. The Author(s).)

Opinion Statement: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated vascular sarcoma. EHE can have different clinical presentations from indolent to rapidly evolving cases, behaving as a high-grade sarcoma. Serosal effusion and systemic symptoms such as fever and severe pain are known as adverse prognostic factors; however, outcome prediction at disease onset remains a major challenge. In spite of its rarity, an international collaborative effort is in place with the support of patient advocates to increase the knowledge of EHE biology, develop new treatment options, and improve patient access to new active medications. Currently, systemic therapies are indicated only for patients suffering from progressive and/or symptomatic disease and in patients with a high risk of organ dysfunction. Standard systemic agents available so far for treatment of sarcomas, and in particular anthracycline-based chemotherapy, have marginal activity in EHE. On this background, EHE patients should be always considered for clinical study when available. The MEK inhibitor trametinib has been recently investigated prospectively in advanced EHE showing some activity, but the publication of the full dataset is still awaited to better interpret the results. Besides, there are data on response to antiangiogenics such as sorafenib and bevacizumab and, from retrospective studies, interferon, thalidomide, and sirolimus. Unfortunately, none of these agents is formally approved for EHE patients and access to treatments varies greatly between countries causing a huge disparity in patient care from one country to another., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Rationale: Epithelioid hemangioendothelioma (EHE) is a rare, low to moderate-grade malignancy, even less in pulmonary endovascular neoplasm. Patients with pulmonary EHE have no optimal treatment, resulting in poor prognoses., Patient Concerns: We reported a 42-year-old man with multiple mild metabolic uptakes in pulmonary endovascular filling defect with a maximum standardized uptake value of 4.5 by 18-fluorodeoxyglucose/fibroblast associated protein inhibitor-positron emission tomography/ computed tomography. Anticoagulant treatment was not effective with the diagnosis of acute pulmonary embolism., Diagnoses: A primary endovascular EHE pulmonary endovascular epithelioid hemangioendothelioma was diagnosed by endovascular biopsy with positive stains for molecular CD31, CD34 and CAMTA1, and it had low proliferative capacity characterized by Ki-67 of 5%. The mutation gene MSH2 (p.Y656 in exon 12) (mutation abundance of 0.07%) from peripheral blood indicates the potential benefit of an immune checkpoint inhibitor, pembrolizumab., Interventions and Outcomes: The patient was treated with tri-weekly paclitaxel (175mg/m2) and carboplatin (AUC 5) chemotherapy regimen. He exerted a remarkable response after 5 cycles (21 days per cycle) and Pembrolizumab (200mg once monthly) as maintenance treatment., Lessons: This case highlights the diagnostic challenge of differentiating endovascular lesions and optimal therapy for pulmonary EHE. Importantly, it indicated that the mutation gene MSH2 (p.Y656) might influence the pathogenesis of EHE., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. The authors report the case of a young woman diagnosed with PEH. DNA and RNA analysis by next-generation sequencing was performed on the tumor tissue. A novel germline PALB2 mutation and classical  WWTR1-CAMTA1 fusion were identified. She experienced a poor response to sintilimab (a PD-1 inhibitor) plus platinum-based chemotherapy as the first-line treatment. PEH patients harboring a germline PALB2 mutation and WWTR1-CAMTA1 gene fusion may respond poorly to treatment with PD-1 inhibitors plus chemotherapy.

Purpose: A consistent genetic alteration in vascular cancer epithelioid hemangioendothelioma (EHE) is the t(1;3)(p36;q25) chromosomal translocation, which generates a WWTR1(TAZ)-CAMTA1 (TC) fusion gene. TC is a transcriptional coactivator that drives EHE. Here, we aimed to identify the TC transcriptional targets and signaling mechanisms that underlie EHE tumorigenesis., Experimental Design: We used NIH3T3 cells transformed with TC (NIH3T3/TC) as a model system to uncover TC-dependent oncogenic signaling. These cells proliferated in an anchorage-independent manner in suspension and soft agar. The findings of the cell-based studies were validated in a xenograft model., Results: We identified connective tissue growth factor (CTGF) as a tumorigenic transcriptional target of TC. We show that CTGF binds to integrin αIIbβ3, which is essential for sustaining the anchorage-independent proliferation of transformed NIH3T3/TC cells. NIH3T3/TC cells also have enhanced Ras and MAPK signaling, and the activity of these pathways is reduced upon CTGF knockdown, suggesting that CTGF signaling occurs via the Ras-MAPK cascade. Further, pharmacologic inhibition of MAPK signaling through PD 0325901 and trametinib abrogated TC-driven anchorage-independent growth. Likewise, for tumor growth in vivo, NIH3T3/TC cells require CTGF and MAPK signaling. NIH3T3/TC xenograft growth was profoundly reduced upon CTGF knockdown and after trametinib treatment., Conclusions: Collectively, our results demonstrated that CTGF and the Ras-MAPK signaling cascade are essential for TC-mediated tumorigenesis. These studies provided the preclinical rationale for SARC033 (NCI 10015-NCT03148275), a nonrandomized, open-label, phase II study of trametinib in patients with unresectable or metastatic EHE., (©2022 The Authors; Published by the American Association for Cancer Research.)

Epithelioid hemangioendothelioma (EHE) is a very rare vascular tumor, originating from endothelial cells. The etiology of EHE is unknown, yet at the molecular level, different angiogenic stimulators may act as promoters of endothelial cell proliferation. The tumor affects more commonly the lung, the liver and the bones but it can affect any other organ. Due to its heterogeneous presentation and its rarity it is often misdiagnosed. No treatment is proved to be efficient in metastatic EHE and the median survival of patients with metastatic pleural disease is generally poor, less than one year. we report a case of a 57-year-old female with multiple metastatic EHE including pleural, diagnosed by medical thoracoscopy, with a progression-free survival of 24 months with oral vinorelbine as maintenance therapy after combination of cisplatin-vinorelbine. We believe that this therapy might be of value to test in this patient population as it has never been tested before.

Purpose: Tumors with neomorphic mutations in IDH1/2 have defective homologous recombination repair, resulting in sensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. The Olaparib Combination trial is a phase II, open-label study in which patients with solid tumors harboring IDH1/2 mutations were treated with olaparib as monotherapy, with objective response and clinical benefit rates as the primary end points., Methods: Ten patients with IDH1/2-mutant tumors by next-generation sequencing were treated with olaparib 300 mg twice daily., Results: Three of five patients with chondrosarcomas had clinical benefit, including one patient with a partial response and two with stable disease lasting > 7 months. A patient with pulmonary epithelioid hemangioendothelioma had stable disease lasting 11 months. In contrast, clinical benefit was not observed among four patients with cholangiocarcinoma., Conclusion: These results indicate preliminary activity of PARP inhibition in patients with IDH1/2-mutant chondrosarcoma and pulmonary epithelioid hemangioendothelioma. Further studies of PARP inhibitors alone and in combination in this patient population are warranted.

Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with an unpredictable clinical behavior. Pleural EHEs have been associated with poor response to treatment and reduced survival. To date, no standard treatment for EHE is available. Here we report the case of a 53-year-old man who underwent radical surgery for a symptomatic primary pleural EHE. Clinical presentation was characterized by chronic pain in the left hemithorax with transitory flare, anemia, weight loss and progressive worsening of clinical conditions. After surgery, he resumed active life and normal daily activities and, at 8 months, 18F-FDG PET and computed tomography scan showed no radiological evidence of recurrent disease. Clinical signs of this rare disease, histological features, imaging findings and functional imaging are discussed. We also report a summary of other cases with resected pleural EHE and we briefly review the role of chemotherapeutic, immunomodulatory and antiangiogenic drugs for advanced disease., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Epithelioid hemangioendothelioma (EHE) patients can experience severe pain. Nonsteroidal anti-inflammatory drugs, including ketorolac tromethamine, can effectively treat cancer-related pain, provide an opioid-sparing effect, and may be particularly effective for EHE pain. There are limited data describing prolonged (>5 days) continuous intravenous (IV) ketorolac infusion for cancer-related pain and no data on its use in EHE. Case Description: A 67-year-old woman with metastatic hepatic EHE suffered from chronic intractable pleuritic pain unresponsive to trials of nonopioid, opioid, adjuvant medications, and nonpharmacological interventions. In the hospital, continuous IV ketorolac infusion at 3.8 mg/hour (91.2 mg/day) effectively managed pain. With thorough monitoring, the patient was discharged on continuous IV ketorolac infusion at 3 mg/hour (72 mg/day). Infusion continued for 79 days without clinical or laboratory evidence of ketorolac toxicity. Conclusion: Ketorolac tromethamine as a long-term infusion is a potentially viable analgesic for patients with intractable EHE-related pain unresponsive to standard therapies.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication., Competing Interests: Disclosure SS: Honoraria, consultancy or advisory role: Adaptimmune, Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, Immune Design, Karyopharm, MaxiVAX, Novartis, PharmaMar; Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AMF: Institutional financial interests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar, SpringWorks. AC: Advisory board: Angelini Holding S.p.A, Shionogi B.V., L. Molteni & C., Kyowa Kirin S.r.l.; invited speaker King Faisal Specialist Hospital & Research Center. JB: Uncompensated advisory board: Novartis; research funding (institutional) from Eli Lilly, Novartis, Roche, Samsung Bioepis Co. Ltd, Paxman Coolers Ltd, Sun Pharma. SB: Personal fees from Bayer, Deciphera, Lilly, Daiichi Sankyo, Plexxikon, Exelixis, PharmaMar, Lilly, Roche, GlaxoSmithKline (GSK); grants from Incyte, grants and personal fees from Blueprint Medicines, Novartis; research funding (institutional) Pfizer. SB: Research support from Novartis, Incyte, Blueprint Medicines; honoraria or consultation fees from Novartis, Lilly, Pfizer, PharmaMar, Bayer. JYB: Research support and honoraria from Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Roche, Bayer, Novartis, GSK, Deciphera, OSE Pharma, AstraZeneca. Member of the supervisory board: Innate Pharma. SB: Honoraria from PharmaMar. JVMGB: Research funding from TRACON Pharmaceuticals; Royalties from UptoDate and Wolters Kluwer. KB: Advisory: Bayer; expert testimony: Bayer; invited speaker: Lilly; institutional research funding: Lilly. TB: Advisory board from Bayer; honoraria: Novartis, PharmaMar, Eli Lilly. ME: Consultant for Blueprint Medicines; advisory boards for Clinigen and Bayer. AF; Honoraria: Amgen, Lilly, Roche, MSD; research funding; MSD, Roche, Clovis, AstraZeneca. BMS; Abbvie. VF: Consulting or advisory role: BMS, MSD, Novartis; speakers' bureau: BMS, MSD, Novartis, Pierre Fabre. XGdM: Advisory boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche, PharmaMar; honoraria from Lilly, Astellas Pharma, Eisai, Pfizer. HG: Reports institutional funding from Novartis, Deciphera. FG: Honoraria from Deciphera, Amgen; stock ownership from Atlanthera; royalties from Zimmer. GG: Grants/research supports: PharmaMar, Novartis, Bayer; honoraria or consultation fees: PharmaMar, Bayer, Merck, Eisai, Novartis, Glaxo. NH: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria and travel grants from PharmaMar; and research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen and Daiichi Sankyo. PH: Honoraria for consultations and speaker's fees from Roche, GSK, AstraZeneca, Pfizer, PharmaMar, Lilly, Nanobiotix, Novartis, EISAI, Nektar, Sirtex and Pekkip Oncology; research funding and educational grants from Novartis, Siemens, Boehringer, Merck, BLUMedicine and Springer; trial support to my institution by Novartis and Siemens. PH: Advisory roles for Sarcoma UK and National Leiomyosarcoma Foundation; research grants from Sarcoma UK, Desmoid Tumor Research Foundation, Children's Cancer and Leukemia Group and Cancer Research UK, funding from EHE Rare Cancer Charity (UK). HJ: Chair of the Orion Pharma Scientific Advisory Board, chair of Neutron Therapeutics Advisory Board; he has been employed by Orion Pharma, and owns stocks of Orion Pharma and Sartar Therapeutics. RJ: Advisory board Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immune Design, Lilly, Merck, PharmaMar, SpringWorks, TRACON, UptoDate; honoraria: BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. CJ: Travel grants from PharmaMar, Ipsen. BK: Reports advisory board Bayer, Blueprint, Boehringer Ingelheim, GSK, PharmaMar, SpringWorks; research funding (institutional) PharmaMar, SpringWorks. AK: Advisory board Otsuka; invited speaker for Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Taiho. ALC: Advisory boards with Lilly, PharmaMar, Deciphera, Blueprint. AL: Reports institutional financial interest, and educational grant from Alphamed, ImplanTec, Johnson & Johnson, Medacta. JMB: Research grants from PharmaMar, Eisai, Immix BioPharma and Novartis; honoraria from PharmaMar, Lilly, Bayer, Eisai, Daichii. Travel grants from PharmaMar; advisory board: Roche, Lilly, PharmaMar; research funding for clinical studies (institutional) from PharmaMar, Eli Lilly and Company, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, Forma, Amgen, Celgene, Pfizer, BMS, and Daiichi Sankyo. OMe: Consultation fees from MSD, AstraZeneca, Takeda, Megapharm, Medison, Progenetics; supported lecture: MSD, AstraZeneca, Roche, BMS. OMi: Consultancy for Amgen, AstraZeneca, Bayer, BMS, Eli Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Servier, Vifor Pharma; Speakers bureau: Eli Lilly, Roche, Servier; Stock ownership: Amplitude Surgical, Ipsen, Transgene. EP: Advisory boards for Amgen, Daiichi Sankyo, Lilly, Deciphera, EUSA Pharma, and SynOx Therapeutics; research support from BMS, Pfizer, PharmaMar, Daiichi Sankyo, Incyte; travel support from Lilly, PharmaMar and Takeda. MAP: Advisory board Lilly, Pfizer, Roche. SP: Consultant: Deciphera, Daichi Sankyo, Dova, Epizyme, MaxiVAX; Research/Grant Support: Blueprint Medicines, Hutchison MediPharma. SPN: Advisory board for Immunocore. AR: Consulting role with Lilly, Merck, Boehringer Ingelheim; research funding from CASI Pharmaceuticals, Boehringer Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Boston Biomedical, BMS, MedImmune, Amgen, GSK, Blueprint Medicines, Merck, AbbVie, Adaptimmune. PRe: Advisory roles for Bayer, Clinigen, Roche, MSD, Deciphera, PharmaMar, Mundibiopharma, and speaker's honoraria from Lilly, PharmaMar. BPR: Reports advisory board from Deciphera. PRu: Advisory board MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Medicines; honoraria from BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. MS: Travel grant from PharmaMar. SJS: Advisory boards for Lilly and GSK. WDT: Reports fees from Eli Lilly, EMD Serono, Eisai, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Blueprint, GSK, Agios Pharmaceuticals, NanoCarrier, Deciphera; patent Companion Diagnostic for CDK4 inhibitors - 14/854 329 pending to MSKCC/SKI, and patent Enigma and CDH18 as companion Diagnostics for CDK4 inhibition – SKI2016-021-03 pending to MSKCC/SKI and Scientific Advisory Board - Certis Oncology Solutions, Stock Ownership Üo-Founder - Atropos Therapeutics; Stock Ownership/scientific advisory board Innova Therapeutics. WTAWDG: Reports consultancy from SpringWorks to her institute; research grant support from Novartis and Lilly to her institute; advisory for Bayer to her institute. AJW: Consulting: Daiichi Sankyo, Deciphera, Epizyme, Mundipharma; research support to my Institution: Aadi Bioscience, Daiichi Sankyo, Deciphera, Eli Lilly, Karyopharm, Plexxikon. PGC: Honoraria, consultancy or advisory role: Bayer, Deciphera, Eisai, Eli Lilly, Pfizer. Institutional financial interest: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme, Glaxo, Hutchinson MediPharma, Karyopharm, Novartis, Pfizer, PharmaMar. APDT: Honoraria: Roche, Bayer, Pharmamar, MSD. AG: Compensations for Advisory boards from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, Nanobiotix; honoraria from Lilly and PharmaMar; institutional research grants from PharmaMar. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions., Methods: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method., Results: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported., Conclusion: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network., Methods: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method., Results: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction., Conclusions: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup., (© 2020 American Cancer Society.)

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor with no standardized treatment. The mammalian target of rapamycin inhibitor, sirolimus, has been used successfully in adult EHE and other vascular tumors in children but has not been studied in pediatric EHE. The aim of this retrospective case series is to discuss the results of sirolimus for treatment in 6 pediatric patients with EHE. Four of 6 patients demonstrated partial response or disease stabilization with sirolimus treatment. No treatment dosing, trough goals, or duration of treatment recommendations can be made. Prospective studies are warranted to further investigate the use of sirolimus in treatment of EHE.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor originating from endothelial cells. Clinical aspect of the disease covers a wide spectrum from a low-grade tumor to a fatal cancer. Most common sites of EHE are reported as lung, liver and bone. Hepatic EHE (HEHE) is a clinical form with an incidence of less than 1 person in a million. Due to rarity of the disease, there is no standard therapy established. Surgery and liver transplantation still seem to be the best approach if possible. However, most of the patients present with unresectable or metastatic disease. Many conventional chemotherapeutic agents and antiangiogenic drugs have been reported previously in the literature with inconsistent outcomes. Here we report 4 cases of HEHE, who benefit distinctly from anti-VEGF treatments in different settings. While combination of paclitaxel and bevacizumab resulted in partial response in 3 patients, one of them also achieved long-term disease stabilization with bevacizumab maintenance with no adverse event. Two of the patients had clear benefit from pazopanib during the course of disease. One patient was treated with thalidomide for 18 months with stable disease, and is still being followed without any treatment. Although targeting VEGF-VEGFR pathway seems to be the best approach in HEHE, randomized studies are urgently needed to support these findings., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Pseudomyogenic hemangioendothelioma (PMHE) is a rare endothelial neoplasm that involves the bones in only 14% of all cases. The optimal treatment strategy has not been established. We herein report a case of primary PMHE in which denosumab treatment showed activity in both imaging studies and the clinical outcome., Case Presentation: A 20-year-old woman presented with worsening pain in her left ankle. Imaging studies showed multifocal fluorodeoxyglucose (FDG)-avid [maximum standardized uptake value (SUVmax), 15.95] osteolytic lesions in the bones of her left lower extremity. While waiting for the definitive pathologic diagnosis of PMHE, denosumab, a human immunoglobulin G2 monoclonal antibody against RANKL, was initiated to treat progressive bone absorption after curettage of one of the lesions. Denosumab induced osteosclerosis around the lesions and pain relief and was discontinued 4 years after its initiation. Although all of the multifocal lesions remained, they all became less FDG-avid (SUVmax, 2.6), and the patient developed no signs of new lesions or distant metastasis., Conclusion: Denosumab plays a certain role in prevention of bone destruction by PMHE through suppression of osteoclast-like giant cells and would be an excellent treatment for bone absorption by PMHE of bone.

Introduction: Epithelioid hemangioendothelioma (EHE) of the bone is a very rare malignant vascular neoplasm, with biologic behavior between that of locally aggressive epithelioid hemangioma and malignant epithelioid angiosarcoma. We report a case of a patient with EHE who underwent bone scintigraphy, try to identify the characteristics of it, to highlight the clinical importance of whole-body bone scintigraphy and single-photon emission computed tomography/computed tomography (SPECT/ CT) in the diagnosis and treatment of EHE., Patient Concerns: A 67-year-old man with no history of trauma who reported pain in both lower limbs for 6 months, which had been worsening over the last 20 days. Anteroposterior and lateral radiographs of both lower limbs revealed numerous osteolytic lesions in the tibia and fibula bilaterally. Tc-methylene diphosphonate (MDP) bone scintigraphy demonstrated increased tracer uptake in the pelvic and bilateral lower limb bones. SPECT/CT bone imaging showed numerous osteolytic lesions cluster in the same anatomic region, with high tracer uptake in lesion margins., Diagnosis: EHE of the bone., Interventions: Two months after the diagnosis was confirmed, the patient was rehospitalized. Nonopioid analgesic use had not provided pain relief. Magnetic resonance imaging (MRI) of both thighs showed the bone cortex was destroyed with numerous irregular lesions, and soft-tissue was involved. A second bone scintigraphy did not show any new lesions. He was administrated with recombination human endostatin injection 15 mg ivgtt qd for 14 days, combined with apatinib mesylate tablets 500 mg po qd for 18 days., Outcomes: He was discharged voluntarily and died 2 months later., Conclusion: EHE of the bone is a very rare malignant vascular neoplasm with no specific radiographic imaging features. Whole-body bone scintigraphy, especially SPECT/CT bone imaging, significantly reduces ambiguous diagnoses and is recommended before treatment.

Pseudomyogenic hemangioendothelioma (PMH) is a rare, mostly indolent, endothelial neoplasm of low-grade malignancy, often mimicking myoid and epithelioid tumors histologically. It is more frequent in young adult males and it usually presents with multiple cutaneous nodules, mostly localized at the extremities. It traverses several tissue planes simultaneously and can involve dermis, subcutis, skeletal muscle, and bone. Histologically, it is characterized by plump spindle cells with eosinophilic cytoplasm, often arranged in fascicles and epithelioid cells with "pseudomyogenic" morphology. Immunohistochemically, PMH is positive for Factor VIII, FLI-1, INI-1, vimentin, MDM2, CDK4, CD31, AE1/AE3, EMA, and P63. The efficacy of treatments is only partially known. Because of the frequent multifocal aspect of PMH, which contraindicates surgery, systemic treatments, such as gemcitabine, sirolimus, and everolimus are used. Based on our observation of multifocal PMH of the foot in a 17-year-old male patient, treated with gemcitabine with complete cutaneous response in a 2-year follow-up, we decided to discuss this rare tumor and underline its progression and therapeutic approaches. Thanks to a correct diagnosis, it is possible to avoid aggressive therapeutic approaches, which would be necessary for nonindolent diseases, such as sarcoma, which often needs amputation., (© 2018 Wiley Periodicals, Inc.)

Rationale: Hepatic epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor of endothelial origin with a highly variable clinical presentation and natural history. Given its vascular origin, new therapies with inhibitors of vascular endothelial growth factor (VEGF) have been introduced in the treatment of these patients and have shown promising results. Few reports have described the role of F-Fluorodeoxyglucose positron emission tomography/contrast-enhanced computed tomography (F-FDG PET/CT) in the evaluation of this tumor after treatment with anti-angiogenic agents. Our case reports how F-FDG PET-CT scan was critical in the assessment of this tumor after treatment with an anti-angiogenic agent, Pazopanib, demonstrating complete metabolic response., Patient Concerns: A 30-year-old man with no previous significant medical history presented with pain in the right upper quadrant for over a year., Diagnoses: Multiple hepatic masses were found on abdominal ultrasound. Liver biopsy confirmed the diagnosis of epithelioid hemangioendothelioma. F-FDG PET/CT was performed for staging. Multiple FDG-avid hepatic, splenic, and lymph nodes lesions were detected on F-FDG PET/CT. A subsequent spleen biopsy confirmed splenic involvement. Immunohistochemistry was positive for CD31, CD34, and ERG, supporting the diagnosis of epithelioid hemangioendothelioma., Interventions: A 1-year cyclophosphamide treatment was provided followed by Pazopanib for 17 months., Outcomes: Six years after the first F-FDG PET/CT, F-FDG PET/CT performed for restaging demonstrated complete metabolic response to therapy. Follow-up CT demonstrated no interval changes in size of some of the treated lesions., Lesson: F-FDG PET/CT is useful for baseline assessment and posttreatment follow-up of this rare cancer.

Purpose: Pseudomyogenic hemangioendothelioma (PHE) is an extremely rare locally aggressive neoplasm with endothelial differentiation, which often presents with multiple lesions. These tumors have characteristic SERPINE1-FOSB fusions. We report a 17 years old patient with advanced unresectable PHE with a durable complete remission to the multi-tyrosine kinase inhibitor telatinib. The aim of this study was to generate an in vitro model for PHE, to study the functional consequences of SERPINE1-FOSB in endothelial cells, and its interaction with telatinib, to biologically substantiate the complete response to telatinib. Experimental Design: As the fusion results in overexpression of a truncated form of FOSB, we overexpressed truncated FOSB in normal endothelial cells. Results: Truncated FOSB significantly affected tumor growth in three-dimensional (3D) on matrigel with increased and sustained sprouting. Moreover, truncated FOSB acted as an active transcription factor capable to regulate its own transcription, as well as to upregulate PDGFRA and FLT1 expression (four-fold). Telatinib decreased proliferation and tumor growth in 3D and induced apoptosis. As expected, telatinib blocked VEGF signaling as phosphorylation of ERK was abolished. Interestingly, in FOSB overexpressing cells, telatinib specifically affected PDGFRA, FLT1, and FLT4 signaling and downregulated SERPINE1, thereby affecting the self-regulation of the fusion gene. Conclusions: We provide a biological substantiation of a complete clinical remission that was seen in a patient with PHE, showing that telatinib indirectly interferes with the self-regulated expression of the fusion product. Thus, telatinib or any other currently available VEGFR1-4/PDGFRA inhibitor could be a highly specific treatment option for patients with multifocal unresectable PHE. Clin Cancer Res; 24(11); 2678-87. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Opinion Statement: Epithelioid hemangioendothelioma (EHE) is an extremely rare sarcoma, as such it can pose a clinical dilemma based solely on its rarity. Also, the spectrum of disease varies greatly between an indolent disease and aggressive disease with widespread metastases. In our clinical practice, the primary focus has been to get a handle on the aggressive nature of the disease, which will then dictate how urgently one needs to treat the patient. Pathological review with immunohistochemistry and molecular characterization is paramount. Our treatment strategy is watch-and-wait versus active therapy on clinical trial or based on results of prior clinical trials. There is evidence to support the use of chemotherapeutics and targeted therapies specifically focusing on anti-angiogenesis. The current landscape of oncology with the emergence and excitement of immunotherapy could also translate in a role for immunotherapy in this disease. While rare, there is certainly no reason that research and trials for patients with EHE should not remain on utmost importance for those of us who specialize in the treatment of sarcomas.

Angiosarcoma, epithelioid hemangioendothelioma, and Kaposi sarcoma are classified according to the line of differentiation that these neoplastic cells most closely resemble: the endothelial cell. Although these malignant vascular sarcomas demonstrate immunohistochemical and ultrastructural features typical of this lineage, they vary dramatically in presentation and behavior, reflecting oncologic mechanisms unique to each. Antineoplastic therapies offer significant benefit, but because of the rarity of these cancers, novel therapies are slow to develop, and treatment options for these cancers remain limited. Antiangiogenic approaches that have shown benefit in other malignancies have not fully realized their promise in vascular tumors, suggesting that these tumors do not depend entirely on either angiogenic growth factors or on neighboring endothelia that are affected by these agents. Nonetheless, translational studies have begun to unravel these distinct pathologies, identifying novel translocation products, targets of oncogenic virulence factors, and genomic mutations that hijack angiogenic signaling and drive malignant growth. Concurrently, an elaborate and highly regulated model of angiogenesis and lymphangiogenesis involving vascular endothelial growth factor-receptor tyrosine kinase and TGF-β and Notch pathways has emerged that informs treatment of these tumors as well as cancer in general. This review summarizes the literature on malignant vascular sarcomas in the context of current models of angiogenesis and, in light of recent clinical trial data, could help clinician-scientists generate novel therapeutic approaches.

Rationale: Pulmonary epithelioid hemangioendothelioma (P-EHE) is a rare tumor, with no established standard treatment. Overexpression of vascular endothelial growth factor receptor 2 (VEGFR-2) has been reported in some P-EHE patients. Apatinib, a new small molecule tyrosine kinase inhibitor that specifically targets VEGFR-2, has therapeutic benefits in some advanced tumors. However, its efficacy in P-EHE cases has not been reported., Patient Concerns: Herein, we presented a 44-year-old man with recurrent hemoptysis for approximately 9 years., Diagnoses: After hospitalization, relevant examinations were conducted. The disease was subsequently diagnosed as P-EHE., Interventions: The patient underwent pulmonary lobectomy, but subsequently developed multiple metastases. Within the tumor, CD31, CK, and Vimentin were found to be positive, while CD34 was negative. Apatinib was initially administered 250 mg daily doses and after 1 month was increased to 500 mg daily., Outcomes: He showed noticeable symptomatic improvements and positive imaging changes in the first month of treatment. However, the disease progressed in the following month, despite the increased apatinib dose., Lessons: Apatinib is possibly a new treatment for P-EHE. However, further clinical trials are necessary to confirm an effective dose and the efficacy and safety of apatinib in P-EHE treatment.

Background/aim: Hepatic epithelioid haemangio-endothelioma (HEHE) is a very rare malignant tumor of vascular origin and uncertain biological behaviour that is difficult to diagnose using preoperative radiology diagnostic techniques., Patients and Methods: The authors present here two patients with HEHE of different extent. The first patient had a generalised form of disease, with involvement of the liver, lungs and bones and was treated with a combination of bevacizumab and capecitabine. The second patient had a localised form of disease involving the liver and this was resolved using a combination of liver resection and radiofrequency ablation. In both patients, the radiology work-up before surgery was non-specific and metastases of another malignant process were considered. The definitive histological diagnosis was made by the pathologist on the basis of immunohistochemical analysis that demonstrated the presence of CD31, CD34 and calmodulin-binding transcription activator 1 (CAMTA 1)., Results: Both patients remain in an overall good condition 27 and 5 months respectively following treatment for HEHE., Conclusion: Preoperative radiological diagnosis of HEHE is difficult and immunohistochemical examination of the tumor tissue sample remains the key diagnostic tool. Radical surgical resection or liver transplantation is the method of choice in patients with localised liver involvement., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Epithelioid hemangioendothelioma is a multifocal tumor that rarely metastasizes. It is difficult to diagnose, most often it is an incidental finding in young asymptomatic women. The radiologic pattern is heterogeneous. Histologic confirmation of Weibel-Palade bodies or immunohistochemistry based on specific tumor markers such as factor VIII and CD34 are the most important finding to confirm the diagnosis. We report a 21 years old woman Presenting with cough and dyspnea. A chest X ray was suggestive of tuberculosis. Sputum smears were negative for acid fat bacilli and the tuberculin test was negative. A chest CAT scan showed multiple nodular lesions. A surgical biopsy of the lesions confirmed the presence of a hemangioendothelioma. The patient was initially treated with prednisone and azathioprine without response. Thereafter, the patient is without treatment and without evidence of disease progression.

Background: Pazopanib is a multitargeted tyrosine kinase inhibitor approved for the treatment of patients with selective subtypes of advanced soft tissue sarcoma (STS) who have previously received standard chemotherapy including anthracyclines. Data on the efficacy in vascular sarcomas are limited. The main objective of this study was to investigate the activity of pazopanib in vascular sarcomas., Patients and Methods: A retrospective study of patients with advanced vascular sarcomas, including angiosarcoma (AS), epithelioid hemangioendothelioma (HE) and intimal sarcoma (IS) treated with pazopanib in real life practice at EORTC centers as well as patients treated within the EORTC phase II and III clinical trials (62043/62072) was performed. Patient and tumor characteristics were collected. Response was assessed according to RECIST 1.1. and survival analysis was performed., Results: Fifty-two patients were identified, 40 (76.9%), 10 (19.2%) and two (3.8%) with AS, HE and IS, respectively. The response rate was eight (20%), two (20%) and two (100%) in the AS, HE and IS subtypes, respectively. There was no significant difference in response rate between cutaneous and non-cutaneous AS and similarly between radiation-associated and non-radiation-associated AS. Median progression-free survival (PFS) and median overall survival (OS; from commencing pazopanib) were three months (95% CI 2.1-4.4) and 9.9 months (95% CI 6.5-11.3) in AS, respectively., Conclusion: The activity of pazopanib in AS is comparable to its reported activity in other STS subtypes. In this study, the activity of pazopanib was similar in cutaneous/non-cutaneous and in radiation/non-radiation-associated AS. In addition, pazopanib showed promising activity in HE and IS, worthy of further evaluation.

Background: The aim of this study was to report on sirolimus activity in a series of patients with hemangioendothelioma (HE) treated at the National Cancer Institute, Milan (Istituto Nazionale Tumori; INT) and within the Italian Rare Cancer Network ("Rete Tumori Rari"; RTR)., Methods: We retrospectively reviewed patients with advanced and progressing epithelioid hemangioendothelioma (EHE) treated with sirolimus at the INT and/or within the RTR. Pathologic review and molecular analysis for WWTR1 rearrangement were performed. Sirolimus was administered until unacceptable toxicity or progression, with the dose being adjusted to reach target plasma levels of 15-20 ng/dL. Responses were assessed using the Response Evaluation Criteria In Solid Tumors (RECIST) criteria., Results: Since 2005, 18 patients (17 EHE, 1 retiform HE; 1 locally advanced, 17 metastatic; WWTR1 rearrangement: 16) have been identified, with 17/18 patients being evaluable for response. Mean sirolimus daily dose was 4.5 mg. According to RECIST, best responses in EHE were 1 partial response (PR), 12 stable disease (SD), and 3 progressive disease (PD); the patient with retiform HE also achieved a PR, lasting >2 years. Four patients with a reversed interval progression on interruption were observed. Median overall survival was 16 months, and median progression-free survival was 12 months (range 1-45), with four patients progression-free at 24 months. The clinical benefit (complete response [CR] + PR + SD >6 months) was 56 %. Seven patients receiving sirolimus experienced an increase in pleural/peritoneal effusion plus worsening of tumor-related symptoms; six of these patients died within 1-8 months from evidence of effusion progression, while a RECIST PD was assessed in two of seven patients., Conclusions: A clinical benefit was achieved in 56 % of patients receiving sirolimus, which lasted >24 months in four patients. Most patients with pleural effusion did not benefit from sirolimus and had a poor outcome.

Introduction: Epithelioid hemangioendothelioma (EHE) is a family of blood vessel tumors originating in blood vessels, bone, brain, kidney, liver, and lung. EHE is more common in women, and chemotherapy, radiation, and surgery have brought few successes., Case Presentation: We present a case of a 28-year-old woman whose EHE recurred during pregnancy, suggesting hormonal involvement. We conducted a systematic review to provide analysis and interpretation of the potential significance of her disease recurring, with fatal outcome, during pregnancy., Discussion: Very little research has explored the use of individual hormonal markers. Strongly positive expression of placenta growth factor (PlGF) and 17-beta estradiol receptors have been reported. Expression of PlGF is noteworthy in our case, in that our patient's disease quickly and dramatically flared in the 25th week of pregnancy, near the peak in maternal PlGF production. PlGF binds to vascular endothelial growth factor-1 (VEGF-1), and PlGF may accelerate VEGF-induced angiogenesis. Taken together, these factors may explain our patient's EHE recurrence and rapid flare-up during pregnancy. Treatment of EHE with VEGF inhibition, potentially in combination with other antiangiogenic and tumor-inhibiting therapies such as lenalidomide, thalidomide, sorafenib, and sunitinib, may also hold promise.

Background: Epithelioid hemangioendothelioma is a rare vascular tumor of borderline or low-grade malignancy. The lungs and liver are the two common primary organs affected. Metastatic disease was reported in more than 100 cases in the literature. However, no firm conclusions can be determined for recommended treatment options., Case Presentation: The current case presents a patient with metastatic pulmonary epithelioid hemangioendothelioma to the cervical and mediastinal lymph nodes, lungs and liver that has been treated with pazopanib for more than two years with PET avid complete metabolic response in the mediastinum and lungs, and long-lasting stable disease. Target therapies that block VEGFR have a logical base in this rare malignancy., Conclusions: The current case is the first to report objective, long-lasting response to pazopanib.

Background: Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour, which can arise at any site. There is little published data about the management of these tumours., Patients and Methods: A retrospective review of patients with histologically-proven EHE presenting to the Royal Marsden Hospital from January 1999 to January 2012., Results: Thirty-two patients (23 females) were identified with a median age of 44 (range=17-78). Twenty patients presented with diffuse disease. Median overall survival (OS) was 9.8 years in 10 patients with operable disease. Amongst those with inoperable disease (n=22), patients with liver disease had the longest median OS (9.8 years), while those with lung and mediastinal disease had the shortest OS (3.6 years). A variety of treatments were used for inoperable disease with infrequent radiological responses., Conclusion: The clinical behaviour can vary depending on the site of disease. Surgery, if feasible, has the best outcome. In those with inoperable disease, a period of observation to assess the tumour behaviour is recommended. The role of medical therapy remains unclear., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare hepatic vascular tumor that represents a diagnostic challenge. The rarity of this neoplasm precludes establishment of a standard-of-care treatment. Risk factors for HEHE are not well-known. Liver transplant remains the most common therapeutic modality for nonmetastatic disease. This article describes a patient who presented with abdominal pain, fatigue, poor appetite, and weight loss. Genetic testing showed that the patient was homozygous for C282Y consistent with hereditary hemochromatosis, and liver biopsy was consistent with malignant epithelioid hemangioendothelioma. The patient was referred for a liver transplant but was deemed inappropriate for transplant secondary to peritoneal studding, with frozen-section analysis showing metastatic disease at the time of surgery., (Copyright © 2014 by the National Comprehensive Cancer Network.)

We have carried out a stratified phase II study of sorafenib (So) in patients with advanced angiosarcoma (n = 32) and epithelioid hemangioendothelioma (n = 13). This report concerns the correlative analysis of the predictive values of circulating pro/anti-angiogenetic biomarkers. Using the ELISA method (R&D Systems), circulating biomarkers (VEGF-A, in picograms per milliliter), thrombospondin-1 (TSP1, in micrograms per milliliter), stem cell factor (SCF, in picograms per milliliter), placental growth factor (PlGF, in picograms per milliliter), VEGF-C (in picograms per milliliter), and E-selectin (in nanograms per milliliter) were measured before So treatment and after 7 days. VEGF-A (mean value 475 vs. 541, p = 0.002), TSP1 (16 vs. 24, p = 0.0002), and PlGF (20.9 vs. 40.7, p = 0.0001) significantly increased during the treatment. Treatment did not affect the levels of SCF, VEGF-C, and E-selectin. Only two biomarkers were associated with better outcome as follows: VEGF-A and PlGF. Best objective response and non-progression at 180 days were associated with low level of VEGF-A at baseline (p = 0.04 and 0.03, respectively). There was a correlation between the circulating level of VEGF-A and time to progression (TTP) (r = -0.47, p = 0.001). Best objective response and non-progression at 180 days were not associated with baseline level of PIGF, but there was a correlation between the circulating level of PIGF at baseline and TTP. Low level of VEGF-A at baseline (<500) was significantly associated with better outcome.

Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.

Unlabelled: Epithelioid Hemangioendothelioma (EHE) is a rare aggressive vascular tumor and can occur in almost all locations. Spine location is rare. There are just a few cases published in the literature and the longer series included only five cases., Case Report: We report a case of a 58-year-old woman who presented with anemia and cervical pain without neurological deficit. Radiological diagnosis revealed a C2-C3 mass with vertebral artery involvement and liver metastases. Partial resection and arthrodesis followed by radiotherapy and chemotherapy were performed. Local control of the diseases was achieved but distance metastasis appears two years after surgery., Conclusions: EHE of the spine is extremely rare in clinic as a primary aggressive vascular tumor. Metastatic disease is the most important factor to predict prognosis. It is not clear in the literature which is the best surgical approach in this patients and it mainly depends of the location and systemic illness. En bloc resection or expanded resection supported with adjunct radiation therapy may present with acceptable results of local control of the tumor. Systemic disease control must be achieved with chemotherapy.

Background: Epithelioid hemangio-endothelioma (EHE) is a rare malignant tumor of vascular origin that electively metastasizes to lungs and liver., Case Report: We report the case of a 51-year-old woman with metastatic and progressive EHE of the liver. She was successfully treated with daily administration of sunitinib malate, an oral multi-target tyrosine kinase inhibitor, which particularly targets vascular endothelial growth factor (VEGF) receptors. Stabilization has lasted 6 years. We discuss the rationale for using antiangiogenic treatment for EHE., Conclusion: This case adds to a growing body of evidence that suggests that antiangiogenic agents should be considered in patients who present with advanced EHE.

Vascular sarcomas are soft-tissue tumors that arise from the endothelium with a malignant potential. This review discusses the management of epithelioid hemangioendothelioma (EHE) and angiosarcoma. EHE is a vascular tumor of intermediate malignant potential with an indolent course. EHE arising from the liver, lung, or bone tends to be multifocal and the rate of progression is slow and often unpredictable. Treatment should be considered in patients with significant symptomatic deterioration and/or progressive disease on imaging studies. Various cytotoxic and targeted therapies are available for management, with disease stabilization as the most common outcome. Angiosarcoma is an aggressive vascular tumor with a high malignant potential. Multidisciplinary care is critical for the management of localized disease, and the best outcomes are often observed in patients when a combination of systemic and local therapy options is used. Metastatic angiosarcoma is treated primarily with systemic therapy, and several cytotoxic and targeted therapies are available, alone or in combination. The choice of therapy depends on several factors, such as cutaneous location of the tumor, performance status of the patient, toxicity of the treatment, and patient goals.