An observational study in Clinical Presentation, Natural History and Treatment Outcomes, sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano. Recruiting at 1 site in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-04-01.
Sponsored by Fondazione IRCCS Istituto Nazionale dei Tumori, Milano · Observational
The EHE observational study was developed to obtain a high number of datas such as clinical presentation, natural history, and treatment outcomes, cto identificate cytokines and hormones as biomarkers and generate patient-derived preclinical models as a tool to assess the activity of anticancer agents and validate novel therapeutic targets
Epithelioid hemangioendothelioma (EHE) is an ultra-rare (incidence rate \< 1/1000.000), translocated, vascular soft tissue sarcoma. It shows a pick of incidence in the 4th decade of life, and it is more commonly diagnosed in females, with reported disease onset during pregnancy.
Two specific translocations have been identified in EHE, representing an hallmark in diagnosis today: the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1) which is present in almost 90 % of cases, and the fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3), which can be found in around 10% of the patients. YAP and TAZ are well-defined downstream effectors in the Hippo pathway. Forced activation of YAP/TAZ is thought to drive EHE and contribute to key aspects of the cancer phenotype, including metastasis and fibrosis.
Most of the times, EHE presents as multifocal or metastatic at diagnosis, with lung, liver and bone being the more commonly involved. The clinical course ranges from cases naturally stable over time to those highly aggressive and rapidly fatal. Pleural effusion, lymph node metastases and pathologic features (nuclear pleomorphism, mitotic figures and presence of necrosis) have been reported to be associated with a worse outcome, but biological and molecular predictors are still lacking. In particular, there is a subgroup of EHE presenting with serosal involvement, typically associated with chronic mild fever, weight loss, asthenia, anorexia, severe disease- related pain, (more responsive to anti-inflammatory pain killers that morphine), and dyspnoea which seems to perform very poorly. The biological basis sustaining this presentation is completely unknown.
As of today, there are no reports available in literature providing a comprehensive description of the peculiar EHE radiological features, both for primary and metastatic disease at different sites, and their potential prognostic role has not been explored. In addition, there are no published data to indicate the optimal routine follow-up policy of surgically treated EHE patients with localised disease and the routine follow-up schedules differ across institutions. The appropriate frequency of imaging in cases suffering of distant metastases is also left to be determined.
Also, the definition of radiological progression and the assessment of treatment response in EHE remain major challenges. The appearance or worsening of serosal effusion, the changes in serosal involvement and the limited increase in size over a short-time interval in slow-growing variants are not promptly captured by Response Evaluation Criteria for Solid Tumor (RECIST) definition for disease progression. This makes the use of such criteria unsatisfactory in this complex disease and could potentially lead to a delay in progression recognition and treatment start. Similarly, being frequently observed in EHE under treatment, improvement of serosal effusion, reduction in size \<30%, and correlation between radiology and symptoms should be taken into account when assessing treatment response.
Surgery is the mainstay of care in the local setting. Active surveillance can be a reasonable strategy for patients with naturally stable or asymptomatic, slowly progressive disease, reserving medical treatment to symptomatic or progressive cases.
Data on conventional chemotherapy in advanced EHE are limited to case reports and single-institution experiences and suggest a limited role for the drugs commonly used in adult-type soft tissue sarcomas. Signs of activity have been reported with the use of anti-angiogenics, including pazopanib, sorafenib, bevacizumab, alone or in combination with chemotherapy, and apatinib. Due to the peculiar natural history of the disease, the value of antiangiogenics and/or immunomodulatory agents has also been explored, with responses described with sirolimus, thalidomide, interferon, and celecoxib.
In absence of any active treatment available, EHE is a neglected disease, and the identification of new potentially active compounds, especially for patients affected by the more aggressive EHE variant. To this end, it looks to be of major importance to identify what is behind disease progression, the "inflammatory-like" disease presentation, and the prevalence of the disease in the female young population.
Several lines of evidence have highlighted the significance of inflammation at the local and/or systemic level in human tumor pathobiology. Indeed, inflammation can influence tumor progression, metastasis and therapeutic outcome by establishing a tumor supportive immune microenvironment. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation.
Estrogen signaling is mediated via several receptor proteins. In addition to the classical ERα and ERβ, the membrane-bound G-protein coupled estrogen receptor (GPER) mediates both the genomic and non-genomic effects of estrogen and has been implicated in the development of other tumors such as breast cancer. Interestingly, GPER stimulation activates YAP and TAZ as key effectors of the Hippo pathway. Insulin-like growth factor-1(IGF-1) has also been shown to regulate GPER expression and function, suggesting a crosstalk between growth factors and ERs The availability of translatable preclinical models of human EHE, able to properly recapitulate tumor biology and response to treatment of the clinical tumors, appears instrumental for the development of innovative and effective treatments. Patient-derived xenograft (PDX) models preserve the original histomorphological and molecular characteristics of the originating clinical tumors. We previously demonstrated the consistency between preclinical data obtained on PDXs of different soft-tissue sarcoma histotypes (solitary fibrous tumor, epithelioid sarcoma and dedifferentiated liposarcoma) and clinical results concerning the activity of several cytotoxic and molecularly targeted drugs, providing novel insight into the antitumor effect of different combinations that was instrumental to design novel clinical trials.
MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Their proven deregulation in several types of human cancer, and the possibility to be reliably detected in both tissue and blood specimens, have prompted the assessment of miRNAs as novel cancer biomarkers21. No information is currently available on miRNA expression and function in EHE.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano is the lead sponsor of 172 studies on the registry; 50 are open to participants now.
Counted across the registry records on this site, refreshed daily.
We plan to include at least 50 patients (range: 50-70) in 36 months, followed by a follow up time of 3 years.68 including The Royal Marsden Hospital.
Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Biopsy and archival tissue
A biopsy takes a small piece of tissue to examine. “Archival tissue” is a sample already taken, for example at diagnosis, and kept by the hospital.
Whether a stored sample will do depends on when it was taken, how much there is and what the study needs. Ask whether the study accepts your stored sample or needs a new biopsy.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Patients newly diagnosed with advanced EE starting active surveillance
Patients with new diagnosis of advanced, evolving EE, worthy of medical treatment
Patients with a previous diagnosis of advanced EE, already under active surveillance
Patients with a previous diagnosis of advanced EE with ongoing medical treatment
Patients with localized EHE
Demographic description
To provide a demographic description of the population affected by advanced EHE
Time frame: Through study completion, an average of 1 year
Patient status
To provide a description of clinical presentation, natural history, and treatment pattern in patients with advanced EHE
Time frame: Through study completion, an average of 1 year
Tumor-related symptoms
To provide a description of tumour-related symptoms and their changes over time
Time frame: Through study completion, an average of 1 year
Tumor-related pain
To provide a tumor-related pain assessment
Time frame: Through study completion, an average of 1 year
Clinical prognosis
To prospectively identify clinical prognostic and predictive factors
Time frame: Through study completion, an average of 1 year
radiological features
To describe the radiological features of the disease (group A, B, C, D, E)
Time frame: Through study completion, an average of 1 year
correlation between radiological features and outcome
To correlate radiologic features with the outcome and the tested plasma levels of the cytokines and hormones (group A, B, C, D, E)
Time frame: Through study completion, an average of 1 year
radiological response and systemic treatment
To assess radiologic response to systemic treatments by basing on RECIST 1.1 assessment (group B, D).
Time frame: Through study completion, an average of 1 year
Plan to share: No
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